View source for 7fbp


==FXIIa-cMCoFx1 complex==
<StructureSection load='7fbp' size='340' side='right'caption='[[7fbp]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7fbp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7FBP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FBP FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=7fbp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7fbp OCA], [https://pdbe.org/7fbp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7fbp RCSB], [https://www.ebi.ac.uk/pdbsum/7fbp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7fbp ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FA12_HUMAN FA12_HUMAN] Congenital factor XII deficiency;Hereditary angioedema type 3. Defects in F12 are the cause of factor XII deficiency (FA12D) [MIM:[https://omim.org/entry/234000 234000]; also known as Hageman factor deficiency. This trait is an asymptomatic anomaly of in vitro blood coagulation. Its diagnosis is based on finding a low plasma activity of the factor in coagulating assays. It is usually only accidentally discovered through pre-operative blood tests. F12 deficiency is divided into two categories, a cross-reacting material (CRM)-negative group (negative F12 antigen detection) and a CRM-positive group (positive F12 antigen detection).<ref>PMID:8528215</ref> <ref>PMID:2882793</ref> <ref>PMID:2510163</ref> <ref>PMID:8049433</ref> <ref>PMID:9354665</ref> <ref>PMID:10361128</ref> <ref>PMID:11776307</ref> <ref>PMID:15205584</ref> <ref>PMID:15617741</ref>   Defects in F12 are the cause of hereditary angioedema type 3 (HAE3) [MIM:[https://omim.org/entry/610618 610618]; also known as estrogen-related HAE or hereditary angioneurotic edema with normal C1 inhibitor concentration and function. HAE is characterized by episodic local subcutaneous edema, and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE3 occurs exclusively in women and is precipitated or worsened by high estrogen levels (e.g. during pregnancy or treatment with oral contraceptives). It differs from HAE types 1 and 2 in that both concentration and function of C1 inhibitor are normal.<ref>PMID:16638441</ref> <ref>PMID:17186468</ref> 
== Function ==
[https://www.uniprot.org/uniprot/FA12_HUMAN FA12_HUMAN] Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.<ref>PMID:21304106</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cyclotides are plant-derived peptides with complex structures shaped by their head-to-tail cyclic backbone and cystine knot core. These structural features underpin the native bioactivities of cyclotides, as well as their beneficial properties as pharmaceutical leads, including high proteolytic stability and cell permeability. However, their inherent structural complexity presents a challenge for cyclotide engineering, particularly for accessing libraries of sufficient chemical diversity to design potent and selective cyclotide variants. Here, we report a strategy using mRNA display enabling us to select potent cyclotide-based FXIIa inhibitors from a library comprising more than 10(12) members based on the cyclotide scaffold of Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II). The most potent and selective inhibitor, cMCoFx1, has a pM inhibitory constant toward FXIIa with greater than three orders of magnitude selectivity over related serine proteases, realizing specific inhibition of the intrinsic coagulation pathway. The cocrystal structure of cMCoFx1 and FXIIa revealed interactions at several positions across the contact interface that conveyed high affinity binding, highlighting that such cyclotides are attractive cystine knot scaffolds for therapeutic development.

An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human beta-Factor XIIa in a Cyclotide Scaffold.,Liu W, de Veer SJ, Huang YH, Sengoku T, Okada C, Ogata K, Zdenek CN, Fry BG, Swedberg JE, Passioura T, Craik DJ, Suga H J Am Chem Soc. 2021 Nov 10;143(44):18481-18489. doi: 10.1021/jacs.1c07574. Epub , 2021 Nov 1. PMID:34723512<ref>PMID:34723512</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7fbp" style="background-color:#fffaf0;"></div>

==See Also==
*[[3D structures of FXII|3D structures of FXII]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Craik DJ]]
[[Category: Fry BG]]
[[Category: Huang YH]]
[[Category: Liu W]]
[[Category: Ogata K]]
[[Category: Okada C]]
[[Category: Passioura T]]
[[Category: Sengoku T]]
[[Category: Suga H]]
[[Category: Swedberg JE]]
[[Category: Zdenek CN]]
[[Category: De Veer SJ]]