6ts5

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==Coagulation factor XI protease domain in complex with active site inhibitor==
==Coagulation factor XI protease domain in complex with active site inhibitor==
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<StructureSection load='6ts5' size='340' side='right'caption='[[6ts5]]' scene=''>
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<StructureSection load='6ts5' size='340' side='right'caption='[[6ts5]], [[Resolution|resolution]] 1.29&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TS5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TS5 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6ts5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TS5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TS5 FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ts5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ts5 OCA], [http://pdbe.org/6ts5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ts5 RCSB], [http://www.ebi.ac.uk/pdbsum/6ts5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ts5 ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NW2:2-[2-[3-[(3~{S})-3-azanyl-2,3-dihydro-1-benzofuran-5-yl]-5-propan-2-yl-phenyl]ethoxy]-3-methoxy-benzoic+acid'>NW2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ts4|6ts4]], [[6t7p|6t7p]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">F11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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/Coagulation_factor_XIa Coagulation factor XIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ts5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ts5 OCA], [http://pdbe.org/6ts5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ts5 RCSB], [http://www.ebi.ac.uk/pdbsum/6ts5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ts5 ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[http://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1beta, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients.
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Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor XIa inhibitors: Demonstrating the power of an integrated S1 protease family approach.,Lorthiois E, Roache J, Barnes-Seeman D, Altmann E, Hassiepen U, Turner G, Duvadie R, Hornak V, Karki RG, Schiering N, Weihofen WA, Perruccio F, Calhoun A, Fazal T, Dedic D, Durand C, Dussauge S, Fettis K, Tritsch F, Dentel C, Druet A, Liu D, Kirman L, Lachal J, Namoto K, Bevan D, Mo R, Monnet G, Muller L, Zessis R, Huang X, Lindsley L, Currie T, Chiu YH, Fridrich C, Delgado P, Wang S, Hollis-Symynkywicz M, Berghausen J, Williams E, Liu H, Liang G, Kim H, Hoffmann P, Hein A, Ramage P, D'Arcy A, Harlfinger S, Renatus M, Ruedisser S, Feldman D, Elliott J, Sedrani RC, Maibaum J, Adams CM J Med Chem. 2020 Jun 17. doi: 10.1021/acs.jmedchem.0c00279. PMID:32551603<ref>PMID:32551603</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 6ts5" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Coagulation factor XIa]]
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Renatus M]]
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[[Category: Renatus, M]]
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[[Category: Schiering N]]
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[[Category: Schiering, N]]
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[[Category: Active site directed inhibitor]]
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[[Category: Hydrolase]]
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[[Category: S1 protease]]
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[[Category: Serine protease]]
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[[Category: Structure-based drug design]]

Revision as of 11:32, 26 August 2020

Coagulation factor XI protease domain in complex with active site inhibitor

PDB ID 6ts5

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