3hkj

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[[Image:3hkj.png|left|200px]]
 
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==Crystal structure of human thrombin mutant W215A/E217A in complex with the extracellular fragment of human PAR1==
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The line below this paragraph, containing "STRUCTURE_3hkj", creates the "Structure Box" on the page.
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<StructureSection load='3hkj' size='340' side='right'caption='[[3hkj]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3hkj]] 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=3HKJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HKJ FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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{{STRUCTURE_3hkj| PDB=3hkj | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3hkj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hkj OCA], [https://pdbe.org/3hkj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hkj RCSB], [https://www.ebi.ac.uk/pdbsum/3hkj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hkj ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:[https://omim.org/entry/613679 613679]. It is a very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels.<ref>PMID:14962227</ref> <ref>PMID:6405779</ref> <ref>PMID:3771562</ref> <ref>PMID:3567158</ref> <ref>PMID:3801671</ref> <ref>PMID:3242619</ref> <ref>PMID:2719946</ref> <ref>PMID:1354985</ref> <ref>PMID:1421398</ref> <ref>PMID:1349838</ref> <ref>PMID:7865694</ref> <ref>PMID:7792730</ref> Genetic variations in F2 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 F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM:[https://omim.org/entry/188050 188050]. It is a multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Defects in F2 are associated with susceptibility to pregnancy loss, recurrent, type 2 (RPRGL2) [MIM:[https://omim.org/entry/614390 614390]. 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:11506076</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN] Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.<ref>PMID:2856554</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hk/3hkj_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3hkj ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The thrombin mutant W215A/E217A (WE) is a potent anticoagulant both in vitro and in vivo. Previous x-ray structural studies have shown that WE assumes a partially collapsed conformation that is similar to the inactive E* form, which explains its drastically reduced activity toward substrate. Whether this collapsed conformation is genuine, rather than the result of crystal packing or the mutation introduced in the critical 215-217 beta-strand, and whether binding of thrombomodulin to exosite I can allosterically shift the E* form to the active E form to restore activity toward protein C are issues of considerable mechanistic importance to improve the design of an anticoagulant thrombin mutant for therapeutic applications. Here we present four crystal structures of WE in the human and murine forms that confirm the collapsed conformation reported previously under different experimental conditions and crystal packing. We also present structures of human and murine WE bound to exosite I with a fragment of the platelet receptor PAR1, which is unable to shift WE to the E form. These structural findings, along with kinetic and calorimetry data, indicate that WE is strongly stabilized in the E* form and explain why binding of ligands to exosite I has only a modest effect on the E*-E equilibrium for this mutant. The E* --&gt; E transition requires the combined binding of thrombomodulin and protein C and restores activity of the mutant WE in the anticoagulant pathway.
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===Crystal structure of human thrombin mutant W215A/E217A in complex with the extracellular fragment of human PAR1===
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Mechanism of the anticoagulant activity of thrombin mutant W215A/E217A.,Gandhi PS, Page MJ, Chen Z, Bush-Pelc L, Di Cera E J Biol Chem. 2009 Sep 4;284(36):24098-105. Epub 2009 Jul 8. PMID:19586901<ref>PMID:19586901</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3hkj" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_19586901}}, adds the Publication Abstract to the page
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*[[Thrombin 3D Structures|Thrombin 3D Structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 19586901 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_19586901}}
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__TOC__
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</StructureSection>
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==About this Structure==
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[[3hkj]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HKJ OCA].
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==Reference==
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<ref group="xtra">PMID:19586901</ref><ref group="xtra">PMID:15252033</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Thrombin]]
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[[Category: Large Structures]]
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[[Category: Bush-Pelc, L.]]
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[[Category: Bush-Pelc L]]
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[[Category: Cera, E Di.]]
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[[Category: Chen Z]]
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[[Category: Chen, Z.]]
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[[Category: Di Cera E]]
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[[Category: Gandhi, P S.]]
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[[Category: Gandhi PS]]
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[[Category: Page, M J.]]
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[[Category: Page MJ]]
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[[Category: Acute phase]]
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[[Category: Blood coagulation]]
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[[Category: Calcium]]
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[[Category: Cell membrane]]
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[[Category: Cleavage on pair of basic residue]]
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[[Category: Disease mutation]]
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[[Category: Disulfide bond]]
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[[Category: G-protein coupled receptor]]
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[[Category: Gamma-carboxyglutamic acid]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Kringle]]
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[[Category: Membrane]]
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[[Category: Pharmaceutical]]
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[[Category: Phosphoprotein]]
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[[Category: Polymorphism]]
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[[Category: Protease]]
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[[Category: Receptor]]
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[[Category: Secreted]]
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[[Category: Serine protease]]
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[[Category: Transducer]]
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[[Category: Transmembrane]]
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[[Category: Zymogen]]
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Current revision

Crystal structure of human thrombin mutant W215A/E217A in complex with the extracellular fragment of human PAR1

PDB ID 3hkj

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