7akv: Difference between revisions
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The entry | ==The cryo-EM structure of the Vag8-C1 inhibitor complex== | ||
<StructureSection load='7akv' size='340' side='right'caption='[[7akv]], [[Resolution|resolution]] 3.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7akv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bordetella_pertussis Bordetella pertussis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AKV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AKV FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.6Å</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7akv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7akv OCA], [https://pdbe.org/7akv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7akv RCSB], [https://www.ebi.ac.uk/pdbsum/7akv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7akv ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/IC1_HUMAN IC1_HUMAN] Defects in SERPING1 are the cause of hereditary angioedema (HAE) [MIM:[https://omim.org/entry/106100 106100]; also called hereditary angioneurotic edema (HANE). HAE is an autosomal dominant disorder characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In HAE type 1, representing 85% of patients, serum levels of C1 esterase inhibitor are less than 35% of normal. In HAE type 2, the levels are normal or elevated, but the protein is non-functional.<ref>PMID:12773530</ref> <ref>PMID:7814636</ref> <ref>PMID:3178731</ref> <ref>PMID:2365061</ref> <ref>PMID:2296585</ref> <ref>PMID:2118657</ref> [:]<ref>PMID:1451784</ref> <ref>PMID:1363816</ref> <ref>PMID:8172583</ref> <ref>PMID:7883978</ref> <ref>PMID:8529136</ref> <ref>PMID:8755917</ref> <ref>PMID:14635117</ref> <ref>PMID:16409206</ref> <ref>PMID:22994404</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/IC1_HUMAN IC1_HUMAN] Activation of the C1 complex is under control of the C1-inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein.<ref>PMID:8495195</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertussis, was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8-C1-INH complex determined using cryo-electron microscopy at a 3.6-A resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases.IMPORTANCE The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia. | |||
Molecular Basis for Bordetella pertussis Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex.,Dhillon A, Deme JC, Furlong E, Roem D, Jongerius I, Johnson S, Lea SM mBio. 2021 Mar 23;12(2):e02823-20. doi: 10.1128/mBio.02823-20. PMID:33758081<ref>PMID:33758081</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Deme | <div class="pdbe-citations 7akv" style="background-color:#fffaf0;"></div> | ||
[[Category: Dhillon | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Bordetella pertussis]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Deme JC]] | |||
[[Category: Dhillon A]] | |||
[[Category: Furlong E]] | |||
[[Category: Johnson S]] | |||
[[Category: Lea SM]] | |||