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| <StructureSection load='4az2' size='340' side='right'caption='[[4az2]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='4az2' size='340' side='right'caption='[[4az2]], [[Resolution|resolution]] 2.60Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4az2]] is a 3 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=4AZ2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AZ2 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4az2]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] 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=4AZ2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AZ2 FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9MU:(R)-N-((S)-1-CARBAMIMIDOYL-PIPERIDIN-3-YLMETHYL)-2-(NAPHTHALENE-2-SULFONYLAMINO)-3-PHENYL-PROPIONAMIDE'>9MU</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[4ayv|4ayv]], [[4ayy|4ayy]]</div></td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9MU:(R)-N-((S)-1-CARBAMIMIDOYL-PIPERIDIN-3-YLMETHYL)-2-(NAPHTHALENE-2-SULFONYLAMINO)-3-PHENYL-PROPIONAMIDE'>9MU</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=4az2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4az2 OCA], [https://pdbe.org/4az2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4az2 RCSB], [https://www.ebi.ac.uk/pdbsum/4az2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4az2 ProSAT]</span></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=4az2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4az2 OCA], [https://pdbe.org/4az2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4az2 RCSB], [https://www.ebi.ac.uk/pdbsum/4az2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4az2 ProSAT]</span></td></tr> |
| </table> | | </table> |
| == 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 == | | == Function == |
| [[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> [[https://www.uniprot.org/uniprot/HIR3_HIRME HIR3_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.
| | [https://www.uniprot.org/uniprot/HIR3P_HIRME HIR3P_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. |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoiminomethyl)piperidine (amidinopiperidine) as a weak, but intrinsically selective, thrombin inhibitor. Elaboration of this molecule provided compounds which inhibit thrombin with Ki's in the range of 20-50 nM and with selectivities of 1000-4000 against trypsin. These inhibitor compounds show a new and unexpected binding mode to thrombin. Modification of the central building block and then of one of the hydrophobic substituents led to the discovery of a new family of thrombin inhibitors which has reverted to the former binding mode to thrombin. This last class of compounds shows inhibitory activities in the picomolar range, low toxicity, and a short plasma half life which favors its use for an intravenous application. From this series of thrombin inhibitors, 19f(Ro 46-6240) was selected for clinical development as an antithrombotic agent for intravenous administration.
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| Design and synthesis of potent and highly selective thrombin inhibitors.,Hilpert K, Ackermann J, Banner DW, Gast A, Gubernator K, Hadvary P, Labler L, Muller K, Schmid G, Tschopp TB, et al. J Med Chem. 1994 Nov 11;37(23):3889-901. PMID:7966150<ref>PMID:7966150</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 4az2" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Hirudin 3D structures|Hirudin 3D structures]] | | *[[Hirudin 3D structures|Hirudin 3D structures]] |
| *[[Thrombin 3D Structures|Thrombin 3D Structures]] | | *[[Thrombin 3D Structures|Thrombin 3D Structures]] |
| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| | [[Category: Hirudo medicinalis]] |
| [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Thrombin]] | | [[Category: Banner DW]] |
| [[Category: Arcy, A D]] | | [[Category: D'Arcy A]] |
| [[Category: Banner, D W]]
| | [[Category: Hilpert K]] |
| [[Category: Hilpert, K]] | | [[Category: Winkler FK]] |
| [[Category: Winkler, F K]] | |
| [[Category: Hydrolase-inhibitor complex]]
| |