View source for 9tlg


==Structure of human prothrombinase with meizothrombin==
<StructureSection load='9tlg' size='340' side='right'caption='[[9tlg]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9tlg]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9TLG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9TLG 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]] 3.1&#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=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</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=9tlg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9tlg OCA], [https://pdbe.org/9tlg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9tlg RCSB], [https://www.ebi.ac.uk/pdbsum/9tlg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9tlg ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FA5_HUMAN FA5_HUMAN] Defects in F5 are the cause of factor V deficiency (FA5D) [MIM:[https://omim.org/entry/227400 227400]; also known as Owren parahemophilia. It is a hemorrhagic diastesis.<ref>PMID:10942390</ref> <ref>PMID:12393490</ref>   Defects in F5 are the cause of thrombophilia due to activated protein C resistance (THPH2) [MIM:[https://omim.org/entry/188055 188055]. THPH2 is a hemostatic disorder due to defective degradation of factor Va by activated protein C. It is characterized by a poor anticoagulant response to activated protein C resulting in tendency to thrombosis.<ref>PMID:9454742</ref> <ref>PMID:11435304</ref> <ref>PMID:11858490</ref> <ref>PMID:14617013</ref> <ref>PMID:14695241</ref>   Defects in F5 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:[https://omim.org/entry/600880 600880]. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera.  Defects in F5 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:[https://omim.org/entry/601367 601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.<ref>PMID:15534175</ref>   Defects in F5 are associated with susceptibility to pregnancy loss, recurrent, type 1 (RPRGL1) [MIM:[https://omim.org/entry/614389 614389]. RPRGL1 is a common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.<ref>PMID:11018168</ref> 
== Function ==
[https://www.uniprot.org/uniprot/FA5_HUMAN FA5_HUMAN] Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The prothrombinase complex, comprised of factor (f) Xa and fVa, converts prothrombin to thrombin through sequential cleavage at two sites in a rapid and processive manner. The molecular basis of prothrombin processing is an enzymatical mystery that to solve requires structural insight into how the substrate and intermediate bind to prothrombinase. Here we present two 3.1 A cryo-EM structures of prothrombinase bound to prothrombin and to meizothrombin. The prothrombin complex revealed a surprising interaction between the end of the heavy chain of fVa with exosite I of prothrombin, accounting for 70% of the contact interface. Triggering of the zymogen-to-protease conformational change following cleavage at Arg320 alters all domain-domain and fVa interactions observed for prothrombin, and results in a large-scale rearrangement of meizothrombin that presents the second cleavage site (Arg271) for processing. Together, these structures reveal a remarkable enzymatic mechanism that requires the active participation of the substrate itself, and introduces a new paradigm of 'substrate allostery'.

Prothrombinase processivity is conferred by substrate allostery.,Ustok FI, Faille A, Warren AJ, Huntington JA EMBO J. 2026 Jun;45(11):3954-3977. doi: 10.1038/s44318-026-00782-4. Epub 2026 Apr , 22. PMID:42020574<ref>PMID:42020574</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9tlg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Faille A]]
[[Category: Huntingon JA]]
[[Category: Ustok FI]]
[[Category: Warren A]]