3lc5

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{{STRUCTURE_3lc5| PDB=3lc5 | SCENE= }}
 
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===Selective Benzothiophine Inhibitors of Factor IXa===
 
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{{ABSTRACT_PUBMED_20121197}}
 
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==Disease==
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==Selective Benzothiophine Inhibitors of Factor IXa==
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[[http://www.uniprot.org/uniprot/FA9_HUMAN FA9_HUMAN]] Defects in F9 are the cause of recessive X-linked hemophilia B (HEMB) [MIM:[http://omim.org/entry/306900 306900]]; also known as Christmas disease.<ref>PMID:8295821</ref><ref>PMID:2592373</ref><ref>PMID:2743975</ref><ref>PMID:6603618</ref><ref>PMID:3009023</ref><ref>PMID:3790720</ref><ref>PMID:3401602</ref><ref>PMID:3243764</ref><ref>PMID:2713493</ref><ref>PMID:2714791</ref><ref>PMID:2773937</ref><ref>PMID:2775660</ref><ref>PMID:2753873</ref><ref>PMID:2738071</ref><ref>PMID:2472424</ref><ref>PMID:2339358</ref><ref>PMID:2372509</ref><ref>PMID:2162822</ref><ref>PMID:1958666</ref><ref>PMID:1902289</ref><ref>PMID:1346975</ref><ref>PMID:1615485</ref><ref>PMID:8257988</ref><ref>PMID:8076946</ref><ref>PMID:8199596</ref><ref>PMID:7981722</ref><ref>PMID:8680410</ref><ref>PMID:9222764</ref><ref>PMID:9590153</ref><ref>PMID:9452115</ref><ref>PMID:9600455</ref><ref>PMID:10698280</ref><ref>PMID:10094553</ref><ref>PMID:11122099</ref><ref>PMID:12588353</ref><ref>PMID:12604421</ref> Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide, mutation in position 93 (Alabama) probably fails to bind to cell membranes, mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya OR Hilo) prevent cleavage of the activation peptide. Defects in F9 are the cause of thrombophilia due to factor IX defect (THPH8) [MIM:[http://omim.org/entry/300807 300807]]. A hemostatic disorder characterized by a tendency to thrombosis.<ref>PMID:19846852</ref>
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<StructureSection load='3lc5' size='340' side='right'caption='[[3lc5]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3lc5]] is a 2 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=3LC5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LC5 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]] 2.62&#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=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=IZX:1-{4-[(R)-PHENYL(3-PHENYL-1,2,4-OXADIAZOL-5-YL)METHOXY]-1-BENZOTHIOPHEN-2-YL}METHANEDIAMINE'>IZX</scene></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=3lc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lc5 OCA], [https://pdbe.org/3lc5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3lc5 RCSB], [https://www.ebi.ac.uk/pdbsum/3lc5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3lc5 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/FA9_HUMAN FA9_HUMAN] Defects in F9 are the cause of recessive X-linked hemophilia B (HEMB) [MIM:[https://omim.org/entry/306900 306900]; also known as Christmas disease.<ref>PMID:8295821</ref> <ref>PMID:2592373</ref> <ref>PMID:2743975</ref> <ref>PMID:6603618</ref> <ref>PMID:3009023</ref> <ref>PMID:3790720</ref> <ref>PMID:3401602</ref> <ref>PMID:3243764</ref> <ref>PMID:2713493</ref> <ref>PMID:2714791</ref> <ref>PMID:2773937</ref> <ref>PMID:2775660</ref> <ref>PMID:2753873</ref> <ref>PMID:2738071</ref> <ref>PMID:2472424</ref> <ref>PMID:2339358</ref> <ref>PMID:2372509</ref> <ref>PMID:2162822</ref> <ref>PMID:1958666</ref> <ref>PMID:1902289</ref> <ref>PMID:1346975</ref> <ref>PMID:1615485</ref> <ref>PMID:8257988</ref> <ref>PMID:8076946</ref> <ref>PMID:8199596</ref> <ref>PMID:7981722</ref> <ref>PMID:8680410</ref> <ref>PMID:9222764</ref> <ref>PMID:9590153</ref> <ref>PMID:9452115</ref> <ref>PMID:9600455</ref> <ref>PMID:10698280</ref> <ref>PMID:10094553</ref> <ref>PMID:11122099</ref> <ref>PMID:12588353</ref> <ref>PMID:12604421</ref> Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide, mutation in position 93 (Alabama) probably fails to bind to cell membranes, mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya OR Hilo) prevent cleavage of the activation peptide. Defects in F9 are the cause of thrombophilia due to factor IX defect (THPH8) [MIM:[https://omim.org/entry/300807 300807]. A hemostatic disorder characterized by a tendency to thrombosis.<ref>PMID:19846852</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/FA9_HUMAN FA9_HUMAN] Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
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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/lc/3lc5_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=3lc5 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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On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.
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==Function==
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Structure Based Drug Design: Development of Potent and Selective Factor IXa (FIXa) Inhibitors.,Wang S, Beck R, Burd A, Blench T, Marlin F, Ayele T, Buxton S, Dagostin C, Malic M, Joshi R, Barry J, Sajad M, Cheung C, Shaikh S, Chahwala S, Chander C, Baumgartner C, Holthoff HP, Murray E, Blackney M, Giddings A J Med Chem. 2010 Feb 25;53(4):1473-82. PMID:20121197<ref>PMID:20121197</ref>
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[[http://www.uniprot.org/uniprot/FA9_HUMAN FA9_HUMAN]] Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3lc5]] is a 2 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=3LC5 OCA].
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</div>
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<div class="pdbe-citations 3lc5" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
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*[[Factor IX|Factor IX]]
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*[[Factor IX 3D structures|Factor IX 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:020121197</ref><references group="xtra"/><references/>
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__TOC__
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[[Category: Coagulation factor IXa]]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Beck, R.]]
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[[Category: Large Structures]]
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[[Category: Wang, S.]]
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[[Category: Beck R]]
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[[Category: Blood coagulation]]
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[[Category: Wang S]]
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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: Egf-like domain]]
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[[Category: Gamma-carboxyglutamic acid]]
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[[Category: Glycoprotein]]
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[[Category: Hemophilia]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Hydroxylation]]
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[[Category: Peptidase s1]]
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[[Category: Phosphoprotein]]
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[[Category: Protease]]
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[[Category: Protein-inhibitor complex]]
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[[Category: Secreted]]
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[[Category: Serine protease]]
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[[Category: Sulfation]]
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[[Category: Zymogen]]
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Current revision

Selective Benzothiophine Inhibitors of Factor IXa

PDB ID 3lc5

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