Talk:Serpin

response to ideas, current state of play

All structural figures now added - on reflection I actually think that a TBG image would be better under a TBG page. Table reasonably well referenced Catalytic mechanism figure adapted and added as suggested. I have asked a colleague for an attractive cell biology figure to go at the top of the page More references added through out and some cleanup and wikifying performed (thanks to Arcadian and Kjaergaard) Have some ideas for additional sections - serpin folding, comment on exception to Anfinsens etc, illustrate phylogeny of superfamily, section on fly serpins and worm serpins.

Jcwhizz 09:39, 12 March 2007 (UTC)

Suggested additions to make before request general review

Polymer picture - combine with delta picture (in progress) Add "disease caused by deficiency" to human serpin list Add figure illustrating key serpin regions that are often mutated in human disease (Breach, shutter). Perhaps put in figure with conserved residues highlighted (or is this too specialised?) Expand polymer section and make more general linkages with protein misfolding Illustrate non-inhibitory section with picture of TBG, ligand and binding site highlighted. General cleanup, add a few more references, PMIDs where possible. Any other suggstions? Jcwhizz 00:59, 11 March 2007 (UTC)

In my opinion, the broad content in the serpin page is now scientificaly accurate, up-to-date, reasonably concise and appropriately structured (I have to admit to some bias, however, having written some of it!). I feel that the only major omission is a picture of a model of a serpin polymer (which I am making). I think there is still quite a bit of stylistic correction and cleanup to do. Major references in the field have been added, however, secondary references should probably be added too? I think the time is right for some more general feedback from the MCB comunity, however, I'm unsure how to start the review process. Jcwhizz 09:42, 11 March 2007 (UTC)

Right now the article is very good on the structural stuff, but contains very little about other aspects about serpins. This bias is probably related to the interests of the contributors. We need a beautiful picture to place in the top of the page to catch the interest of the readers. I think we need to show the catalytic cycle of serine proteases as well, showing explicitly where it is interupted. And I think the table should have the protein names as the first column, rather than the genes, since that are the names they are primarily known by... Kjaergaard 10:17, 11 March 2007 (UTC)

Agree with you on the structural bias (have to confess thats my area) and the catalytic cycle. However, there is a huge effort in the serpin community to stop using the "old" serpin names (which and to use the proper nomenclature SERPINA1 etc as the protein name - I will edit the Gene name to read Protein name (which is actually correct). I'll have a think about a beautiful (non structural) picture.

210.49.179.196 11:02, 11 March 2007 (UTC)

What do you think about a really attractively stained picture of a blood clot (appropriate given the large number of serpins involved in clotting / bleeding etc) or alternatively a white blood cell (rich in serpins) - not sure where to source these though as I don't have them myself. I have to confess I thought first about a nice picture of a serpin crystal - though on reflection I realised that possibly may be too structural...:) ?

Jcwhizz 11:29, 11 March 2007 (UTC)

And I'm pretty sure that PAI-1 doesn't inhibit plasmin directly. I don't know if you have a reference claiming this... Kjaergaard 10:20, 11 March 2007 (UTC)

Will check this out

210.49.179.196 11:02, 11 March 2007 (UTC)

Yup - my mistake - fixed

Jcwhizz 11:29, 11 March 2007 (UTC)

previous discussion

Serpin page coming together - some major and minor things to do. Major: 1) Add more figures (polymer). 2) More extensive referencing 3) Brief two liners about the function of each human serpin - for more in depth analysis should link to relevant pages 4) Section on serpin-enzyme complex uptake by LRP-related protein receptor. 5) Section on worm serpins

Minor Add PMID ids to references that do not have them Work out how to assign a unique number to a reference (i.e. so it is not repeated in the bibliography

Jcwhizz 05:26, 7 March 2007 (UTC)

What is the basis for saying that serpins are enzymes? As I understand it they are "suicide substrates". What reaction are they supposed to catalyze? Josh Cherry 23:15, 14 Jun 2004 (UTC)

In the strict sense of the word you're completely right. Perhaps we should revise nomenclature on this. By the way, how would you categorise these articles? JFW | T@lk 09:45, 15 Jun 2004 (UTC)

A topical serpin involved in malaria resistance - in mosquitoes!

The Monday, 24 October 2005 BBC News headline,

Malaria gene 'defends mosquitoes'

http://news.bbc.co.uk/1/hi/health/4370960.stm

...turns out to refer to this paper:

An immune-responsive serpin, SRPN6, mediates mosquito defense against malaria parasites

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16260729

The conclusion states that Anopheles stephensi SRPN6 is either directly or indirectly involved in the parasite-killing process, whereas Anopheles gambiae SRPN6 apparently acts further downstream on parasite clearance by promoting lysis.

(Mosquitoes with SRPN6 expression knocked out were ultra-susceptible to Plasmodium infection; steps are being taken to produce mosquitoes with a constitutively-active SPRN6 gene, to see what effect that has - immune mosquitoes in the wild would equal reduced Plasmodium transmission rates, until either the parasite or the insect evolved round it...)

Anyway, I just thought this might be germane to this article, but as this is the first time I've done anything on wikipedia, methought it better merely to mention it here so people can see what they think.

Cheers, Tommy B.

It might be more relevant to the Malaria article.... Kjaergaard 18:20, 15 April 2007 (UTC)

Thanks - have pasted it into the Talk:Malaria page, so people there can see what they thank. --Tommy B.

Lead suggestions

The lead has three functions. Firstly, the initial sentence should define the topic clearly and precisely without using too many technical terms. Secondly, the lead should introduce the topic and indicate why it is important. Thirdly, the lead should provide a brief summary of the main points in the article. The lead does an OK job of point one, but is still a bit short for points two and three. Aim for about three paragraphs? Tim Vickers 17:53, 28 July 2007 (UTC)

Hi Tim - good point - have expanded as suggested. Cheers James Jcwhizz 01:43, 29 July 2007 (UTC)

good article review

This is how the article, compares against the six good article criteria:

1. Well written?:

• "and inflammation respectively" needs comma before "respectively"

Done Jcwhizz 00:13, 4 August 2007 (UTC)

• Sometimes a bit verbose -

"The interest in these molecules was initially sparked as a result of their" could be put more succinctly "Initially, research focused on their.."

"While the majority of serpins function to control key extracellular and intracellular proteolytic cascades,..." could be better as "While most serpins control proteolytic cascades,..."

"As a result of their involvement in controlling medically important processes such as coagulation and inflammation, there is considerable interest in serpin function and serpin deficiency." could be better as "As serpins control processes such as coagulation and inflammation, these proteins are the target of medical research."

"The study of serpinopathies is useful for understanding the generalities of protein misfolding, a process that underlies other important human diseases such as Alzheimer’s and prion disease." could be better as "Undertanding serpinopathies provides insights on protein misfolding in general, a process common to many human diseases, such as Alzheimer’s and CJD."

"it is postulated that serpins inhibit both classses" could be better as "serpins may inhibit both classes"

"Analysis of Caenorhabditis elegans serpins revealed that all nine serpin genes lacked signal sequences and these are therefore are proposed to be intracellluar" could be better as "As all nine serpins in Caenorhabditis elegans lack signal sequences, they are probably intracellluar"

"The functional target(s) of intracellular inhibitory serpins have been more challenging to elucidate than their extracellular counterparts." could be better as "In contrast, the targets of intracellular inhibitory serpins have been more difficult to identify."

• Over-use of the word "can" makes prose appear indecisive, "antitrypsin deficiency can cause emphysema", if this phenotype has high penetrance, just say "antitrypsin deficiency causes emphysema"
• As a general rule, try to avoid the passive, past tense. It can make even these fascinating proteins appear very dull!

eg - *"in order to inhibit" is better as "when they inhibit" or "as they bind proteases, these proteins undergo a dramatic..." active, present tense makes most things read clearer and better.

• You never need to say "have been shown to do X" or "studies have shown that X" or "recent research has demonstrated that X" all these phrases do not make your meaning any clearer but only add superfluous and distracting words. Just say "they do X" or "X is"
• "Serpins also possess an exposed region termed the reactive centre (or site) loop (RCL) that (for inhibitory molecules)" - Too many parentheses (by far)!
• "concomittently" - we're writing for the general public, "at the same time" or "simultaneously" are more widely-understood words.
• "PAI-1 is released in the native conformation, however, rapidly undergoes conformational change" - I don't think this says what you intended.

Have gone through, made all the changes requested above, and also edited to make the article more succinct. Jcwhizz 00:13, 4 August 2007 (UTC)

2. Factually accurate?:

• I've not come across "Archae" before, isn't Archaea the more usual term?

Sorry - spello. Jcwhizz 00:13, 4 August 2007 (UTC)

• "These enzymes are defined by the presence of a serine residue in their catalytic site." Many, if not most enzymes contain at least one serine in their active site (which is where the link goes). It is the nucleophilic serine in the enzymatic reaction mechanism that defines this class.

Added the term nucleophilic to make this distinction for both serine and cysteine. Jcwhizz 00:13, 4 August 2007 (UTC)

• "the lack of precise synteny between human serpins and the serpins of model organisms such as the mouse complicates functional characterisation." I don't understand this, if sequence similarity is high enough gene order is irrelevant, if order is conserved but sequence diverges,you can't assume shared functions. Surely sequence is more important than synteny?

Have replaced with functional orthology. Basically the problem is that the murine repotoire of serpins is vastly expanded with respect to human serpins. So for example, where there is one human gene for SCCA-1, there are 3-4 in the mouse. Thus it is difficult to know which one to knock out to gain an understanding of the role of the human protein. Jcwhizz 00:13, 4 August 2007 (UTC)

• "cytotoxic granule protease granzyme B" is this an example of inappropriate intracellular activation of proteases? The way it follows this statement makes me suspect this, but the example doesn't explain enough for me to be sure.

Yes, in certain cases, for example in Tcell killing, there may be some "leakage" of Granzymes during granzyme delivery which are most likely mopped up by serpins such as PI-9. Have changed text to clarify this. Jcwhizz 00:13, 4 August 2007 (UTC)

• I don't think allosteric modulators are often referred to as "cofactors", as this term is usually reserved for compounds required for an enzymatic activity. You could just say "binding of activators and inhibitors"

In this instance I think it is appropriate to - within the serpin field the term co-factor is generally accepted and used to describe molecules that modulate serpin inhibitory activity. See for example, Frank Church's recent review (Rau et al., J Thromb Haemost. 2007 Jul;5 Suppl 1:102-15) - but there many other papers on this topic. Jcwhizz 00:13, 4 August 2007 (UTC)

3. Broad in coverage?:

• Yes.

4. Neutral point of view?:

• A bit pro-serpin! :) but OK

Yes, I have to confess I have an interest :) Jcwhizz 00:13, 4 August 2007 (UTC)

5. Article stability?

• Not a concern.

6. Images?:

• The images are great, but the captions are a bit on the long side. Perhaps some of the text discussing the images, rather than just giving the components and colouring might be moved to the text?

Yes, good point - have shortened all legends, and moved the text of figure 4 (function of heparin) into the text. I have left the odd sentence to really emphasize key points. Jcwhizz 00:13, 4 August 2007 (UTC)

I've put this nomination on hold while the minor text changes are made. If you feel that this review is in error, feel free to take it to a GA review. Thank you to all of the editors who worked hard to bring it to this status. Tim Vickers 21:41, 31 July 2007 (UTC)

Thanks once again for a great and detailed review. Are you happy with the changes? Cheers James Jcwhizz 00:13, 4 August 2007 (UTC)

Very happy, congratulations it is a Good Article! Tim Vickers 14:13, 4 August 2007 (UTC)

Thanks Tim - excellent!! - I'll have a read on what is required for nomination for FA. Cheers James Jcwhizz 22:11, 4 August 2007 (UTC)

As a pointer for FA, the main areas to improve are the lack of a simple organisation, with structure and function interspersed, as well as the prose, which is still written for a specialist audience. I've always imagined FA science articles as aiming for Scientific American/New Scientist level of approachability. Perhaps the closest FA to this topic is the one on DNA, that might give some useful comparisons? Good luck and good writing! Tim Vickers 23:09, 4 August 2007 (UTC)

Problem with Figure 3

Figure 3, "Catalytic mechanism of serine proteases" - The reaction mechanism has some problems. The nitrogen in the carboxamide kinda disappears in the last couple steps and seems to maybe be replaced with an oxygen... —Preceding unsigned comment added by 65.67.67.220 (talk) 22:10, 8 November 2007 (UTC)

The cleaved product leaves the active site then water comes in to complete hydrolysis of the acyl enzyme intermediate. Not sure what problem you are refering to - looks like a pretty standard depiction of the reaction mechanism to me.

Jcwhizz 23:04, 9 November 2007 (UTC)

I made a modified version of the figure, is this any clearer? Tim Vickers 23:51, 9 November 2007 (UTC)

Hi - thats great!! Jcwhizz 08:37, 13 November 2007 (UTC)

I love this page. I added a short description of the uterine serpins with a link to a new page I wrote on them. I hope that is OK. If not, please delete or modify. Ufpete (talk) 12:06, 3 December 2010 (UTC)

Split to reduce size

Article is large and slow to format. It has over 170 references. Should we split it ?
Would it be sensible to split out Table 1 (which alone has over 70 references) ? Rod57 (talk) 09:12, 20 April 2011 (UTC)

Hi - I would be strongly against splitting it or splitting out table 1- basically the page is designed to give a comprehensive and well referenced overview of the serpin superfamily - table 1 is valuable because it gives a quick at a glance insight into the human serpins, which are of primary interest from a medical research perspective. James Whisstock (talk) 12:06, 13 September 2011 (UTC)

How to move this to FA

In response to a previous question by Jcwhizz of how to move this article to FA. Here are my suggestions (some of which I shall try to implement myself over the coming weeks).

Content

• The first section should probably be Activity and be about what they do i.e. inhibit proteases

 Done

• Historical information scattered through the article and lead should be gathered into a single section

 Done I've moved the current historical info into a single section. Will need some more key dates in there (e.g. First discovered serpin? First structure?)

• Lead should only summarise info from elsewhere in the article (and ideally proportionately to the size of each section)

 Done I've removed unique information down to various sections of the article and tried to include a sentence or two on each main section

• The lead image should be the simplest to understand. From my limited knowledge, the PZI/PZ complex isn't the most common situation

 Done I've made a new image for the lead that I hope includes the key points of a serpin

• Several structure sections should be subsections under a general Structure section

 Done

• Similarly, the pathology sections should be grouped under one heading

 Done

• I'll actually semi-disagree with Tim Vickers here are suggest that the captions should describe the key point that the reader should understand from it (from the 2007 GA review)
  • E.g it's not immediately obvious what the significance of the current Fig.12 is just from its caption
  • I think it should still be possible to keep these succinct if a general audience is kept in mind

 Done Tried to write short captions that highlight the specific point that the image is trying to convey.

• The Types and Disease sections could both be shortened by 20-40% to retain balance with the rest of the article

 Done Types section neatened and shortened by default collapse of megatable

 Done I've rearranged the Disease section so that the simpler-to-understand mechanisms of disease are given first

• There were 5 paragraphs and an image on the A-sheet model of polymerisation before it was then stated that it's thought to not be physiologically relevant.

 Done I've removed it for now since it seems heavily over-weighted for a model that is no longer thought to be relevant. I think t that's reasonable given that this is not a historical review of overturned theories, but an encyclopedic summary of what is though to be the correct. I've saved the text below in case I'm missing something obvious though!

A-sheet polymerisation model

Figure 9: Model illustrating the ideas behind the proposed A-sheet mechanism of serpin polymerisation.Chang WS, Whisstock J, Hopkins PC, Lesk AM, Carrell RW, Wardell MR. (1997). "Importance of the release of strand 1C to the polymerization mechanism of inhibitory serpins". Protein Sci. 6 (1): 89–98. doi:10.1002/pro.5560060110. PMC 2143506. PMID 9007980.{{cite journal}}: CS1 maint: multiple names: authors list (link)</ref> The A β-sheet is in red. The RCL (magenta) of the orange molecule is inserted into the bottom of the A-sheet of the white molecule. In the absence of definitive structural data, it was, therefore, postulated that serpins polymerise via a mechanism known as A-sheet polymerisation. In normal function the RCL inserts into the A β-sheet to form a fourth strand. In the A-sheet polymerisation model, it was suggested that the RCL of one serpin molecule spontaneously inserted into the A-sheet of another, to form a long-chain polymer (figure 9). In effect, it was, thus, proposed that polymerization occurred as a consequence of the requirement of the serpin scaffold to accept an additional β-strand. Serpins were one of the first families for which disease-causing mutations were directly analyzed in reference to the available crystal structures. In support of the A-sheet polymerisation model, it was noted that many serpin mutations that cause polymerisation localise to two distinct regions of the molecule termed the shutter and the breach. The shutter and the breach contain highly conserved residues, underlie the path of RCL insertion, and are proposed to be important for conformational change. Two structures of cleaved serpin polymers have been solved; both of which reveal RCL / A-sheet sheet linkages similar to those predicted by the A sheet polymerisation mechanism. However, in direct contrast to the known properties of physiological serpin polymers, crystals of cleaved serpin A-sheet polymers readily dissociate into monomeric forms. Events associated with serpin polymerisation occur during the folding of the molecule, and that mutations that cause serpinopathies interfere with the ability of the serpin to fold to the metastable native state. In normal serpin folding, the serpin rapidly moves through a key folding intermediate to attain the native state. It is the serpin folding intermediate that has the ability to polymerise, hence it is important that this folding species rapidly moves on to adopt native state. Mutations such as the Z-antitrypsin variant (Glu 342 to Lys) somehow prevent the final stage of seprin folding and cause the accumulation of the folding intermediate. As a result, population of the folding intermediate resulted in polymer formation. It was noted that once folded, the Z-antitrypsin variant closely resembles wild-type material in terms of thermal stability and inhibitory activity. Together, these data have presented an important challenge to the A-sheet model for serpin polymerisation. On the one hand, the idea that serpin polymer formation essentially takes advantage of the serpin mechanism of conformational change is an attractive one. On the other, the biophyiscal data in particular suggest that it is a folding intermediate (rather than the native form) that polymerises, and it is clear that this intermediate must have different structural properties to the native, folded state. It is thought that physiological serpin polymers do not form via the A-sheet mechanism, but instead form via more extensive domain swapping events. References

Style

• The page still contains a lot of scientific review-isms
  • e.g. "It should additionally be noted that..." / "Early studies on serpins revealed that..." (removal doesn't change the sentence)
  • e.g. "Rawlings et al. showed that..." (The researcher is irrelevant in this sentence, and is amply covered by the reference)

 Done Reworded most of the main review-style statements.

• References to specific figures aren't really part of the style (since the number and order can change over time) and ideally the images stand alone anyway

 Done I've gone through all of the cations to try to capture the key point being illustrated by the figure, whilst still retaining colour and PDB information.

• I agree that the classification mega-table should stay, but we could use a collapsed table to ease readability of the rest of the page (like in the catalytic triad article)

 Done and also a few formatting changes to it

• The word serpin doesn't need to appear in the section headings

 Done

• Terms like 'recently' make the page harder to keep up to date. Dates can be used, or the recentness can be omitted all together

 Done Important dates could maybe be included in the History section

• PDB codes should be auto-formatted by a template (more robust and easier to edit)

 Done Have used {{PDB}} template in figure legends and {{PDB2}} in the table

• PDB codes not in figure legends should probably be footnotes for the main text, since they're basically references

 Done although there was actually only one occurrence in the end which later turned out to be redundant.

• Images should ideally have white backgrounds and full-resolution version should be >1000px wide.

 Done I've updated several of the key images early in the article.

Optional

• Since the unique mechanism of these proteins is so visually striking, an animation would be ideal. However, this entirely depends on availability of something that can be put under a creative commons copyright license

With these changes, I think it'd be reasonable to submit it for FA nomination and see what the reviewers identify. Although it looks like a lot, I don't think it'll take too much to fix up these bits and pieces. T.Shafee(Evo﹠Evo)^talk 11:27, 1 November 2015 (UTC)

Summary of changes (Nov-Dec 2015)

I've managed to do most of the big changes that I identified above (before and after changes).

The main changes have been:

• Rearrangement of the main headings to better group information
• General language simplification
• First sentences of all sections should be layman-understandable (hopefully)
• Updates of images to better highlight key points
• Removal of figure numbers and more descriptive captions

I've also taken the liberty of updating some of the images. Hopefully they're clearer. T.Shafee(Evo﹠Evo)^talk 05:53, 20 December 2015 (UTC)

To be addressed by a serpin expert

1. When were the first serpins discovered, and when was the first structure solved?

The term serpin is generally accepted in the field to have been coined by Robin Carrell and Jim Travis in 1985 ([1]) - however, proteins such as antitrypsin, antithrombin and ovalbumin have been known since the 19230's and probably earlier. Indeed, the first report of the protease inhibitory activity in human plasma dates (to my knowledge) to 1894

Fermi C, Pernossi L. Untersuchungen uber die enzyme, Ver- gleichende Studie. Z Hyg Infektionskr 1894;18:83e9.

The relationship between different serpin family members became apparent in the early 1980's with this classic paper Biochem Biophys Res Commun. 1980 Jul 31;95(2):864-71.

A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor. Hunt LT, Dayhoff MO.

Also notable is the work of Doolittle - angiotensinogen being a strikingly diverged family member.

Angiotensinogen is related to the antitrypsin-antithrombin-ovalbumin family. Doolittle RF. Science. 1983 Oct 28;222(4622):417-9.

First crystal structures:

Human alpha 1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function. Loebermann H, Tokuoka R, Deisenhofer J, Huber R. J Mol Biol. 1984 Aug 15;177(3):531-57.

Its interesting to note that this was the cleaved form of antitrypsin - there likely would not have been the initial interest in the family if the native form was determined first - the fact that the region supposed to interact with the target protease was buried was a huge surprise and suggested a major conformational change.

The next two structures were in the S state - one of cleaved plakalbumin - which does not undergo the S to R transition and then the first native serpin solved by Penny Stein - ovalbumin.

Crystal structure of plakalbumin, a proteolytically nicked form of ovalbumin. Its relationship to the structure of cleaved alpha-1-proteinase inhibitor. Wright HT, Qian HX, Huber R. J Mol Biol. 1990 Jun 5;213(3):513-28.

Crystal structure of ovalbumin as a model for the reactive centre of serpins. Stein PE, Leslie AG, Finch JT, Turnell WG, McLaughlin PJ, Carrell RW Nature. 1990 Sep 6;347(6288):99-102.

2. Are most serpin-related diseases due to polymerisation or inactivity? From the information balance in the article, currently it looks as though pathologies due to merely inactive serpins are rare.

Most serpin-related disease are linked to polymerisation - however, since polymerisation results in an inactive serpin, many aspects of serpinopathies relate to loss of proper control of proteases - the classic being alpha one - liver disease caused by polymers in the ER, lung disease through failure to properly control elastase.

3. Are there any pathologies of over-active serpins?

None that I'm immediately aware of - I'll have a think though.

4. Is anything known about the evolution of non-inhibitory serpins? Does the RCL have an intersting role in any of them or are they just inert storage/ carrier proteins?

Absolutely - see the section of CBG and TBG - both bind hormones tightly in the stressed form and less tightly in the Relaxed conformation. Other non inhibitory sermons, for example, HSP47 seem to function just in the S state.

5. Is there anything interesting to be said about how the high-energy stressed state is produced by the ribosome? E.g. a sentence in the Structure section.

This question is complex and relates to folding mechanism. No ribosome studies have been done to my knowledge, however, from the perspective of how the S state folds, I like to think of it as a race between getting to native, and alternatively forming polymer. I think latent is reached through native, although this is incompletely understood.

I'll add to the above list if I think of any more things! T.Shafee(Evo﹠Evo)^talk 11:08, 13 December 2015 (UTC)

Responses by Jcwhizz 09:36, 25 December 2015‎

Thanks for the answers Jcwhizz. I've updated the article where appropriate to reflect them. T.Shafee(Evo﹠Evo)^talk 03:09, 1 January 2016 (UTC)

Featured Article nomination

Discussion transcluded from Wikipedia:Featured article candidates/Serpin/archive1

The following is an archived discussion of a featured article nomination. Please do not modify it. Subsequent comments should be made on the article's talk page or in Wikipedia talk:Featured article candidates. No further edits should be made to this page.

The article was promoted by Ian Rose via FACBot (talk) 13:03, 11 March 2016 [2].

---

Serpin

Nominator(s): T.Shafee(Evo﹠Evo)^talk 03:40, 1 January 2016 (UTC)

This article is about a protein superfamily that is significant to both fundamental science (protein conformational change and enzyme inhibition) and applied science (mutations cause a wide array of Genetic disorder). It has been a Good Article since 2007, and has been significantly improved since then (particularly images, layout, readability and accessibility to lay audience). There are relatively few high-quality articles on protein superfamilies currently, so it would be good to have an FA example. T.Shafee(Evo﹠Evo)^talk 03:40, 1 January 2016 (UTC)

Comments from delldot ∇.

Hi Evo & Evo, looking good so far, although I'm only partway through. Thought I'd leave these comments to let you get started. Mostly minor copy editing stuff:

• Might it make sense to add into the first sentence or para what organisms they occur in? e.g. "Serpins are a superfamily of proteins with similar structures, found in all kingdoms of organisms, that were first identified for their protease inhibition activity."

Done - Good point, although I've put their occurrence second in the sentence since it seems the subsidiary point of the sentence.

• I dunno if you can do anything about this, but the first para says "inhibit" so much the word starts to lose its meaning.

Done - I've inhibit managed inhibit to inhibit reduce inhibit the inhibit occurences inhibit a inhibit little. A keen eye could perhaps excise one or two more.

I replaced one with 'acts on', now that's a normal number of 'inhibits'! delldot ∇. 06:38, 6 January 2016 (UTC)

• In History, why is this a new para? "Examples of cross-class inhibitory serpins..." My understanding is short paras are discouraged.

Done - (suspect you mean Activity section) I've combined the paragraphs, since they were clearly discussing the same topic.

• Citations needed: "It is presently unclear whether any mammalian serpins function to inhibit caspases in vivo." "Structural biology has therefore played a central role in the understanding of serpin function and biology." "Around the same time, the first structures were solved..." and "The structures indicated that the inhibitory mechanism involved..."

I'll address these over the next week. Some are easy. A couple I'll have to look up.

Done - The caspase sentence has been removed, since it was an overemphasis on caspases, which held no particular significance in that section. The rest have had references added (or reviews repeated from elsewhere)

• In Protease inhibition, the last sentence seems like a non sequitur. Could there be transition wording or could it be incorporated elsewhere? "In Caenorhabditis elegans, all serpins lack signal sequences..."

Done - I think it was originally included as an example of intracellular serpins, but it's was simultaneously over-specific and vague so I'v moved it down to the Distribution section.

• In structure, Reactive Centre Loop is inconsistently capitalized.

Done

• Why the switch from plural to singular? "Serpins are classed as irreversible inhibitors and a suicide inhibitor"

Done

• Can you replase one 'basis' with another word? "The understanding of the molecular basis of this interaction formed the basis of the development..."

Done - definite improvement

• in Latent conformation, does this exist only in proteins that do not have the described in the previous section, or do some proteins do both?

To the best of my knowledge, latency and activation are relatively rare and no serpins have been described that show both. Jcwhizz may know more.

Ah so this is instead, not in addition. Does that go without saying, or should that be indicated? delldot ∇. 06:38, 6 January 2016 (UTC)

Done - Aha, antithrobin can do both (convert to latency, and be allosterically activated by a cofactor). I've therefore updated the section to make clear that both are possible for the same serpin.

• The section Deficiency is very short. Could it be fleshed out with any examples?

In progress

I'm not a stickler for the cosmetic stuff so I won't object to the two-sentence paragraph, but it would be good to have examples of the conditions that can result, as the other subsections have. delldot ∇. 06:38, 6 January 2016 (UTC)

Done - Whilt looking for more examples it became clear that deficiency almost invariably refers to deficiency due to polymerisation. The few examples of null mutants or less active mutatnts I've now grouped together into a single subsection. I've made clear at the beginning of the Disease section and Polymerisation subsection that polymerisation is the most common mechanism of serpin-caused disease

• Inconsistent spelling of α-Antitrypsin deficiency.

Done

• Unclear: "Each monomer of the serpin aggregate in the relaxed conformation (RCL inserted into the A-sheet)."

Done

• Unnecessary 'in'? "The domain-swapped trimer (of antitrypsin) forms in via the exchange of..."

Done

• I think 'and / or' is discouraged. Would 'and' work just as well by itself here? "Lung and / or liver transplantation is also used to treat"

Done - Hadn't noticed that one! "And" is definitely sufficient.

• "gene targeting in induced pluripotent stem cells has successfully been deployed to correct the Z-antitrypsin defect..." This is the only mention of the Z-antitrypsin defect, can it be described or linked?

Done - I think the term can be safely removed and left as the more descriptive "antitrypsin polymerisation defect"

In general I have no major complaints! Well done making this tough-to-comprehend topic understandable! delldot ∇. 04:28, 4 January 2016 (UTC)

Thanks for the points so far. I've addressed most of them. the ones that require some more reading I'll try to get to over the week. T.Shafee(Evo﹠Evo)^talk 11:41, 4 January 2016 (UTC)

Looking good so far! I replied to a couple of your replies. (Oh, BTW, I think the {{done}} template is discouraged on this page, see the blue box up top). I will be back soon with more input. delldot ∇. 06:38, 6 January 2016 (UTC)

A few more:

• "Antitrypsin augmentation therapy is approved for severe..." Could this sentence be expanded a bit to explain what Antitrypsin augmentation therapy is? Do they just pump a bunch of it into you?

Done - turns out basically yes, not even recombinant currently, jut purified from donor plasma.

• In Degradation, I think it might help to add a topic sentence up front to help introduce and transition to the new topic. Something like, "once a serpin has successfully formed a complex with its target enzyme, it must be broken down and disposed of."

Done

• I think the Signalling section needs to be fleshed out a bit. It might also make sense to move it above Degradation, since wouldn't it seem more logical for the latter to come at the end? But do these really need to be separate sections? What if Conformational change in non-inhibitory function were broadened to be, like, Other things that serpins also do? The signalling seems like it could follow that para. Then the whole article might flow better: How they function in cells, why it's bad when they don't, evolution. Not sure if this would work, just an idea.

Done - I added some more information, then realised that it's really two different phenomena that already have logical places to merge. Where signalling is merely due to the cleave of signalling cascade proteases, I've merged the info into the Function section. Where signalling is due to direct binding of the R-conformation, I've merged it into the Conformational change in non-inhibitory functions section. Degradation is now under the normal functioning, before the Disease section.

Gotta sleep, more later! delldot ∇. 07:13, 6 January 2016 (UTC)

Last few:

• In Human, might it be better to spell out 'about' or 'roughly' rather than a tilde? "analysis of ~500 serpins from 2001".

Done

• I like the idea of hiding the massive table in a navbox collapsed. Might it look better like this rather than having the column headers showing in the title bar?

Done - I've implemented your formatting and moved PDB codes to the end.

• In Insect, does 'toll' need to be capitalized? Should this be hyphenated, Toll-mediated? "...which results in Toll mediated signaling..."

Done - lower case is correct, and hyphenated is appropriate

• In Plant, could "the most well-studied example" be written "the best studied example"? delldot ∇. 01:54, 7 January 2016 (UTC)

Done

Nice job so far! Just one additional comment:

• "The presence of serpins in plants has long been recognised,[166] indeed, an abundant barley grain serpin (barley protein Z) is one of the major protein components in beer." I think this sentence carries a false implication, that recognising serpins and putting them in beer are linked. I'm picturing like the ancient Egyptians or whoever going "aren't these serpins great? Let's put them in beer!" I think just splitting into two sentences and removing the 'indeed' would fix this.

Anyway, ping me when you're done with all my comments, looks like you're super close! delldot ∇. 07:13, 10 January 2016 (UTC)

Excellent work, everything above is addressed. I read it again so of course I now have more comments (don't worry, there's fewer each time!).

• Is this supposed to be capitalized? "a large Extracellular multiprotein complex" I changed one before noticing this one and being overcome by self-doubt. also, maybe a link for extracellular?

Done - must have been a copy-paste error some time back

• The Non-inhibitory roles section is smallish. Is there another sentence that could be said about this? "heat shock serpin HSP47 is a chaperone, essential for proper folding of collagen." What role does it play?

Done - elaborated on HSP47 and added in ovalbumin to make the section cover all non-inhibitory serpins with reasonably well-established function

• Is this correct hyphenation? "In some serpins, the S-to -R transition"

Done

• "polymers are slowly removed via endoplasmic reticulum associated degradation." Should this be "endoplasmic-reticulum-associated" or "endoplasmic reticulum-associated"?

Done - wording order change improves clarity anyway

• The ref Acosta 2015 uses semicolons instead of commas between author names. Same with Mushunje 2004 and Walenga 2002 (also names not initials) and Fermi 1984 (and aren't you supposed to fill a parameter for what language the source is if it's not English?) Also some titles capitalize every word (e.g. de Serres 2002 and Egeberg 1965) and most don't.

Are there semi-automated editing help tools? I'll go through the ref formatting manually if not, but it might be more efficiently done by others!

Real minor stuff. It's promotable now, so I'll go ahead and give my support now on the assumption that you'll do whatever's best with these last few. I did some minor copy editing, you may want to double check it though. delldot ∇. 18:51, 14 January 2016 (UTC)

Comments from Jfdwolff

I'm impressed by the current state of the article (I created its first version in March 2004...) Well done to Evolution and evolvability (and of course to Jcwhizz who has contributed significantly to the content). This is well outside my professional scope so my comments will be limited. JFW | T@lk 16:47, 4 January 2016 (UTC)

• My main concern is about the decision to use primary sources as support for many statements. For clinical articles we are quite strict about secondary sources, although I am fully aware that this is less of a concern for the basic sciences. Is there any scope for increasing reliance on secondary sources? I am worried that claims about transcortin deficiency "caus[ing] chronic fatigue" might be misinterpreted, and I would suggest that all associations with human disease are supported with WP:MEDRS-compatible secondary source whenever possible.

I see your point (particularly the megatable, which contains almost 50% of the total references). I'm not usually involved in MED articles, but the disease section and table of human serpins definitely fall within the remit of WP:MEDRS, so I'll put that as a priority. For these sections (and much of the rest of the article), there are a half dozen or so extensive reviews cited that can be used to support more of the paragraphs to increase the weighting of secondary sources.

Done (maybe) - I've replaced all lead citations with major secondary sources. I've also made sure that all main points made in the Disease section are supported by a secondary source as well as any primaries. Finjally, I've addeed the two main secondary sources for the megatable in its heading. In fact the megatable has a high degree of overlap with the tables presented in both of those references. If appropriate, I'd prefer to keep the primary refs in the table, mostly so that as new functions are discovered, they can be easily added. I'd particularly value your opinion on the use of the main secondary sources in the column name of the the deficiency column of the megatable.

• Other point: consistency of capitalisation in the "Decription" column of the "Table of human serpins", and occasionally in "Common name" and "Disease / Effect of deficiency".

Done - I've gone though and made a stack of clarity and consistency edits. I find it easy to miss those sorts of things in tables.

• In the same table: what is "Angiodemia"?

Done - wow, it's amazing how long a typo can go unrecognised.

Response from T.Shafee(Evo﹠Evo)

@Delldot and Jfdwolff: I've gone through all of the comments above! Let me know if you think the responses sufficient, or if you recommend any further changes. The article is already much improved from your suggestions. One final question is what are your opinions of the External links section? Lists of laboratories seem to be common in science articles, but I'm never sure how well they are kept up to date, or weighted by significance. Finally, I've taken the liberty of emailing the lab heads on that list to see if any are willing to cast their eye over the article before it finishes review. T.Shafee(Evo﹠Evo)^talk 11:46, 14 January 2016 (UTC)

Comment on lead from Aa77zz

Why is it considered necessary to have citations in the lead of this article? The usual practice is to include citations only for direct quotations. See WP:LEADCITE. Aa77zz (talk) 12:18, 15 January 2016 (UTC)

I must admit, I was unaware of the WP:LEADCITE policy! The citations are the broadest academic reviews on the topic, a decision based the decision on WP:MCB articles like DNA, gene and enzyme. It seems to be relatively common for science articles to use the lead to place important general references (list of WP:MCB articles of FA-class). However, given this isn;t anything close to official policy, I'm happy to go with consensus of a few editors (delldot, Jfdwolff - any opinions?). T.Shafee(Evo﹠Evo)^talk 23:45, 15 January 2016 (UTC)

My understanding is there is no rule against putting citations in the lead, and you need them if the info is not cited elsewhere in the article, but they're optional as long as it is. I can't think of any reason to keep them out, but I'm not worried either way. delldot ∇. 02:18, 16 January 2016 (UTC)

Comments from User:Seppi333

• Support promotion to FA – this is one of the best formatted FA candidates that I've gone through in terms of article layout and text formatting. I've manually checked the article source for MOS:NUMERAL, MOS:NBSP, and MOS:IMAGE (specifically, MOS:ALT and MOS:CAPTION) compliance and made a few minor tweaks. I also used AWB to group named refs together and used 2 scripts to standardize MOS:DATEFORMAT and MOS:DASH formatting. I also made a few minor copyedits to the article text. As far as I can tell, the text/source formatting is fully MOS-compliant at the moment.

Here is a summary of my changes.

I'm not entirely familiar with the subject matter of the article, so I'm not particularly comfortable with doing a thorough review of the article text; however, on a cursory read-through the text does appear coherent and well-written. Seppi333 (Insert 2¢) 14:15, 16 January 2016 (UTC)

Comments from User:jcwhizz

• Support promotion to FA – I declare a conflict of interest in that I contributed to earlier versions of the serpin page. I work in the serpin field, and I can confirm to the best of my knowledge that the data in the page is a high quality and accurate reflection of the field and is up-to-date. I'd also like to say that as a total non expert in terms of creating and editing wiki pages that I'm incredibly impressed with how the community (and in particular User:Evolution and evolvability) have worked on this page to make it more attractive and accessible! All the best, James Whisstock.

Response 2 from T.Shafee(Evo﹠Evo)

Thank you to the recommendations, and edits delldot, Jfdwolff, Aa77zz. I believe that all the major points above have now been resolved (or at least discussed). Please let me know if there are any outstanding points you'd like further addressed. T.Shafee(Evo﹠Evo)^talk 05:47, 28 January 2016 (UTC)

Evolution and evolvability I'm still not very happy with some of the sources. Only secondary ones are suitable for medical associations. The "chronic fatigue" reference is unchanged... JFW | T@lk 21:05, 28 January 2016 (UTC)

@Jfdwolff: Ah yes, I'd thought that putting the secondary refs up in the header would be sufficient. I might need I've made a few alternative referencing formats of the megatable in a sandbox page:

1. Version with only secondary sources in header, primaries in cells - new functions easily added when discovered
2. Version with both primary and secondary source for each cell - messy, but ensures that anyone who looks at the primary source ref is fully aware of the secondary source
3. version with secondary references in header only - removes temptation to rely on primary sources, but I can imagine new functions being added to the table with no sources at all

Originally, I was keen to retain the primary sources in addition to the secondary and so preferenced #1, but I guess that any 'new functions' should only be added once there's a suitable secondary review of them anyway! Additionally, the wording of functional descriptions could be made more specific, e.g.:

Deficiency may cause chronic fatigue → Deficiency-causing mutations associated with chronic fatigue

What do you think of the different table versions and wording suggestion? Thanks for your help! T.Shafee(Evo﹠Evo)^talk 02:04, 30 January 2016 (UTC)

Evolution and evolvability I don't think we need the primary sources mentioned at all, provided the secondary source provides the serpin-disease association. I am happy to yield to a second opinion, but formally speaking WP:MEDRS applies. Sorry to be such a nuisance! JFW | T@lk 17:24, 31 January 2016 (UTC)

Incidentally I agree with the wording change. Association does not prove causation. JFW | T@lk 17:26, 31 January 2016 (UTC)

@Jfdwolff: Not a nuisance at all, it's important to get it right. I've implemented the secondary source only table in the article I'll store the current version of the table in this talk page for reference in case anyone needs to chase down a primary reference for some reason. T.Shafee(Evo﹠Evo)^talk 12:16, 1 February 2016 (UTC)

Sorry but I really, really disagree - fair enough cite a secondary source for medical condition, but in in a lot of cases the primary citations ARE important and relate to scientific findings where primary sources can and should be cited - the maspin entry for example is now incorrect, and removing valid information that actually is useful to the community simply because one doesn't want to cite a primary source seem odd and non-helpful. User:Jcwhizz - James Whisstock.

OK - I'm not expert enough a user to undo all that has been done to the table without causing utter mayhem! I think it is essential that primary sources in the table are cited for scientific findings - these make reference to valid peer reviewed papers that usually are published in high profile journals. I am happy for secondary sources to be cited for diseases. So we don't get into a game of tennis and prior to attempting to re-reference the table does this seem reasonable to all?. User:Jcwhizz - James Whisstock.

@Jcwhizz and Jfdwolff: I've had a think about this and I have a possible solution. I agree that it would be a shame to sacrifice the utility of the references for the non-medical statements by just citing secondary sources. What's more, the main secondary sources () are from a biochemistry research angle rather than a medical angle, so aren't actually ideal for WP:MEDRS anyway.

What I suggest is to ensure that all medical claims are kept only in a "Human disease" column, and are only kept if good secondary/tertiary sources can be found for them. Mouse models etc should be kept in a different column so that their relevance to humans is clearly distinguished (and primary sources are still permissible). That way the statements that need to be WP:MEDRS-compliant are more clearly delineated within the table. I've implemented what I mean in the article for now, with disease statements removed until I find good sources for each. I'll add them back in as I go. T.Shafee(Evo﹠Evo)^talk 12:19, 5 February 2016 (UTC)

Evolution and evolvability Thanks, and sorry for the hassle! JFW | T@lk 12:26, 5 February 2016 (UTC)

I think it's important, and worth it to get it right for an FA. Given that the superfamily has such biochemical and medical relevance, it's actually pretty unique as an FA. I hope that resolving it will set a good precedent for other similar articles in the future. T.Shafee(Evo﹠Evo)^talk 12:32, 5 February 2016 (UTC)

OK I have some more thoughts for the ones that you need support for. SERPINB6 - this is pretty clear cut. First of all KO in the mouse results in hearing loss - see PMID: 23669344, so that at least can be cited and mentioned in the table. There are about 4 different studies on various populations that show association of SERPINB6 with human hearing loss - all primary I guess - maybe also cite PMID:20451170 and PMID:25817395 in effect of deficiency section. SERPINB7 was a major discovery and actually very interesting - there are a couple of reviews - PMID: 25029323 and PMID: 24635962. SERPINC1 is antithrombin - heaps and heaps of reviews to choose from here - PMID: 21781239 would be a recent one, but it is one of the best characterised serpins to date. SERPENT (PAI-1) is clearly controversial - think leave this one out in the disease column. SERPINH1 got a cracker here - PMID: 25007323 and PMID: 23145505 - very high profile reviews - again really interesting and unexpected discovery as well. SERPINI1 - very well known if rare disease (FENIB) - see PMID: 12112652 for e.g. or PMID: 19164889. Finally PMID: 25660269 for SERPING1 or PMID: 24125136 - again this should not be controversial - G1 is complement C1 inhibitor - well known in angiodemia. PMID: 17768101 for macular degeneration. By the way I do apologise that I'm simply not adding these things by myself - I just feel that I'm likely to do more formatting harm than good!!!!! As soon as my grant writing season is over I'll try to relearn how to do wiki pages properly. OK - over and out will look at the remainder later. User:Jcwhizz - James Whisstock.

Thanks for the medical review references James. I've integrated them into the megatable, in addition to a good review of the SERPINF2 (α2-antiplasmin). The remaining serpins (A10, B8, I2) seem to have only primary references at the moment. similarly, SERPINA10 (PZI) still seems highly contentious. It's reviewed in '07, but an '08 meta-analysis disagrees.. We should probably leave them out for now, until their disease role is reviewed in the medical literature. T.Shafee(Evo﹠Evo)^talk 05:13, 21 February 2016 (UTC)

Hi - I am really really happy with all this - it is great - all my concerns have been addressed!!!! User:Jcwhizz

Comments from Opabinia

• Support! I've been meaning to read this forever and it looks like everyone else has beaten me to criticisms of any substance :) Well written and illustrated as usual, and very deserving of an FA star. Minor nitpicks/suggestions below. Opabinia regalis (talk) 06:29, 23 February 2016 (UTC)
  • A few instances of "conformation change" - to my ears it should always be "conformational".
  • History section says The name "Serpin" was first coined in the 1980s when it became clear that they formed a large superfamily of related proteins that also included non-inhibitory members - which gives the impression that the name was chosen due to the non-inhibitory members - but the lead says the name is from "serine protease inhibitors", the opposite implication.
  • In the protease inhibition section, preventing modulating activity of protease is awkward.
  • It sounds as if the key to this inhibition mechanism is the kinetics: the conformational change happens faster than acyl hydrolysis. Have the rates actually been measured? Are there mutants that are slow switchers and therefore ineffective inhibitors?
  • Degradation of extracellular serpins is mentioned, but not intracellular - is there anything interesting to say about how these are recycled? (It would be kind of cool if there were a ubiquitination site only exposed post-transition...)
  • Parallelism in the distribution subheads ("fungal", "prokaryote" - pick either nouns or adjectives)

Done - Thanks! I've addressed the wording suggestions. As for the kinetics question, you're completely correct. For wild-type serpins, the relative rates of (inhibition)/(hydrolysis)≈1 i.e. inhibition is so much faster than hydrolysis that the relative rates can't be measured. I get the impression that it's at least 10<sup3-fold faster given the accuracy of the methods used to measure, but I can't find a secondary source that makes the statement. I've added a sentence highlighting the significance of the kinetics. There are plenty of mutants with reduced conformation change rates, but I think that those details are probably too much for the article. V. interesting though! It also turns out that there are multiple, definable sub-steps in the conformational change. T.Shafee(Evo﹠Evo)^talk 21:09, 24 February 2016 (UTC)

Interesting, thanks! I guess one thing I learned today is that acyl hydrolysis is slower than I would've thought. Opabinia regalis (talk) 02:51, 25 February 2016 (UTC)

References

Response 3 from T.Shafee(Evo﹠Evo)

Thank you again to all delldot, Jfdwolff, Aa77zz, Seppi333, Opabinia regalis, and Jcwhizz. I think I've now addressed everyone's key recommendations and criticisms. In particular, I think the combination of primary/secondary sources for scientific points with med-secondary and tertiary sources for medical points has made the page more robust. Again, let me know if there are any additional issues, or if you feel I've not fully addressed the issues already raised! T.Shafee(Evo﹠Evo)^talk 21:20, 24 February 2016 (UTC)

• Suppport FA. Great work. Could I recommend one slightly different source for the clinical correlate of SERPING1 deficiency: doi:10.1016/j.autrev.2015.03.006. The source currently supporting the link with hereditary angiooedema is mostly a cohort study. Otherwise very good work and ready for the star. JFW | T@lk 06:05, 25 February 2016 (UTC)

Coord note

T.Shafee(Evo﹠Evo), is this your first FAC? A belated welcome if so -- we will need a spotcheck of sources for accurate use and avoidance of close paraphrasing in that case. Also source review for formatting and reliability, and image licensing review. All these can be requested at the top of WT:FAC. Cheers, Ian Rose (talk) 23:14, 27 February 2016 (UTC)

@Ian Rose: Thanks, FAC is surprisingly different to the GA system! I've added a source audit request at WT:FAC. Are there any other steps I need to take, or will the rest of the process run its course automatically if the article passes source review? Thanks again, T.Shafee(Evo﹠Evo)^talk 15:03, 28 February 2016 (UTC)

Hi, per my initial comment, pls add "image review" to your list of requests at WT:FAC (unless the licensing has already been validated and I missed it). As long as all these checks come back clean (or any issues found can be actioned in reasonably short order) then there should be nothing more to do before the article can be promoted. Cheers, Ian Rose (talk) 22:59, 28 February 2016 (UTC)

P.S. I note several duplicate links in the article. Given the length and technical nature of the article, some of these might be justified but pls review in any case (you can install and run this script to highlight the duplicates). Cheers, Ian Rose (talk) 23:10, 28 February 2016 (UTC)

Thanks. I've corrected the request. I've also done a run through removing duplicate wikilinks (certainly those in the same section). Some concepts are introduced broadly in e.g the lead or mechanism, but then discussed in more detail in a later section, so the duplicate link is occasionally useful. T.Shafee(Evo﹠Evo)^talk 18:05, 29 February 2016 (UTC)

Source and image review by Cas Liber

Ok, taking a look....

Refs should all be formatted the same - hence the authors of refs (using this version for reference) 8,11, 12, 53, 156, 157 and 163 (and some others) should all be "Smith J, Jones F, etc"

pageranges in refs should be consistent - hence ref 105 has "1269–1275" and ref 40 has "579–586" (also ref 101) - where in most other places you seem to have a two digit page range (e.g. ref 100 has "237–45")

some dates are written "2013-07-01" and some are "March 2002" - I'd comform them all.

Dates have been standardized to DMY. Seppi333 (Insert 2¢) 17:46, 10 March 2016 (UTC)

FN 1 used 5 times - material cited and faithful to source

FN 19 used 3 times - material cited and faithful to source

FN 66 used 6 times - material cited and faithful to source

FN 190 used twice - material cited and faithful to source

FN 192 used once - material cited and faithful to source

Regarding images, if File:Serpin (stressed).png is actually the synthetic scorpion toxin linked to, should it not say that in the description?

Same goes for File:Serpin and protease.png and File:Serpin equilibrium.png

Eep, my mistake: PDB: 2K9O​ should be PDB: 1K9O​! T.Shafee(Evo﹠Evo)^talk 23:25, 10 March 2016 (UTC)

Closing comment

I'm going to promote but pls note there are several duplicate links in the article; some may well be justified given the article's length and detail but pls review and lose whatever's superfluous. This script can be installed and invoked to highlight the duplicates. Cheers, Ian Rose (talk) 13:01, 11 March 2016 (UTC)

• Closing note: This candidate has been promoted, but there may be a delay in bot processing of the close. Please see WP:FAC/ar, and leave the {{featured article candidates}} template in place on the talk page until the bot goes through. Ian Rose (talk) 13:03, 11 March 2016 (UTC)

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