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| - | | + | #REDIRECT [[6eo8]] This PDB entry is obsolete and replaced by 6eo8 |
| - | ==Crystal structure of thrombin in complex with a novel glucose-conjugated potent inhibitor==
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| - | <StructureSection load='4n3l' size='340' side='right' caption='[[4n3l]], [[Resolution|resolution]] 1.94Å' scene=''>
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| - | == Structural highlights ==
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| - | <table><tr><td colspan='2'>[[4n3l]] is a 3 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=4N3L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4N3L FirstGlance]. <br>
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| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2FN:N-(2-{[5-(5-CHLOROTHIOPHEN-2-YL)-1,2-OXAZOL-3-YL]METHOXY}-6-[3-(BETA-D-GLUCOPYRANOSYLOXY)PROPOXY]PHENYL)-1-(PROPAN-2-YL)PIPERIDINE-4-CARBOXAMIDE'>2FN</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
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| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</scene></td></tr>
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| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] </span></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4n3l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n3l OCA], [http://pdbe.org/4n3l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4n3l RCSB], [http://www.ebi.ac.uk/pdbsum/4n3l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4n3l ProSAT]</span></td></tr>
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| - | </table>
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| - | == Disease ==
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| - | [[http://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN]] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:[http://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:[http://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:[http://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:[http://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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| - | [[http://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> [[http://www.uniprot.org/uniprot/HIR3B_HIRME HIR3B_HIRME]] Hirudin is a potent thrombin-specific protease inhibitor. It forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen.
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| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | The beta-d-glucose-containing compound 3, bearing 2-chlorothiophene and 1-isopropylpiperidine moieties as binders of the S1 and S4 pockets, respectively, proved to be potent competitive inhibitor of factor Xa (fXa, Ki = 0.090 nM) and thrombin (fIIa, Ki = 100 nM). The potency of 3 increases, over the parent compound 1, against fIIa (110-fold), much more than against fXa (7-fold). Experimental deconstruction of 3 into smaller fragments revealed a binding cooperativity of the P3/P4 and propylene-linked beta-d-glucose fragments, stronger in fIIa (15.5 kJ.mol(-1)) than in fXa (2.8 kJ.mol(-1)). The crystal structure of human fIIa in complex with 3 revealed a binding mode including a strong H-bond network between the glucose O1', O3', and O5' and two critical residues, namely R221a and K224, belonging to the Na(+)-binding site which may allosterically perturb the specificity sites. The potential of 3 as antithrombotic agent was supported by its ability to inhibit thrombin generation and to stimulate fibrinolysis at submicromolar concentration.
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| - | How a beta-d-Glucoside Side Chain Enhances Binding Affinity to Thrombin of Inhibitors Bearing 2-Chlorothiophene as P1 Moiety: Crystallography, Fragment Deconstruction Study, and Evaluation of Antithrombotic Properties.,Belviso BD, Caliandro R, de Candia M, Zaetta G, Lopopolo G, Incampo F, Colucci M, Altomare CD J Med Chem. 2014 Oct 23;57(20):8563-75. doi: 10.1021/jm5010754. Epub 2014 Oct 14. PMID:25268757<ref>PMID:25268757</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 4n3l" style="background-color:#fffaf0;"></div>
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| - | ==See Also==
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| - | *[[Hirudin|Hirudin]]
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| - | *[[Thrombin|Thrombin]]
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| - | == References ==
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| - | <references/>
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| - | __TOC__
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| - | </StructureSection>
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| - | [[Category: Homo sapiens]]
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| - | [[Category: Thrombin]]
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| - | [[Category: Altomare, C D]]
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| - | [[Category: Aresta, B M]]
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| - | [[Category: Belviso, B D]]
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| - | [[Category: Caliandro, R]]
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| - | [[Category: Candia, M De]]
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| - | [[Category: Complex thrombin-glucose-conjugated inhibitor]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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