5tkt
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((12E,15S)-15-(((2E)-3-(5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL)-2-PROPENOYL)AMINO)-9-OXO-8,17,19-TRIAZATRICYCLO[14.2.1.0~2,7~]NONADECA-1(18),2,4,6,12,16(19)-HEXAEN-5-YL)CARBAMATE== | |
| + | <StructureSection load='5tkt' size='340' side='right' caption='[[5tkt]], [[Resolution|resolution]] 2.12Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5tkt]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TKT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TKT FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7DS:METHYL+((12E,15S)-15-(((2E)-3-(5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL)-2-PROPENOYL)AMINO)-9-OXO-8,17,19-TRIAZATRICYCLO[14.2.1.0~2,7~]NONADECA-1(18),2,4,6,12,16(19)-HEXAEN-5-YL)CARBAMATE'>7DS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tku|5tku]], [[5tks|5tks]]</td></tr> | ||
| + | <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> | ||
| + | <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=5tkt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tkt OCA], [http://pdbe.org/5tkt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tkt RCSB], [http://www.ebi.ac.uk/pdbsum/5tkt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tkt ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[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> | ||
| + | == Function == | ||
| + | [[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. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 muM) and excellent selectivity against the relevant blood coagulation enzymes. | ||
| - | + | Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.,Corte JR, Fang T, Osuna H, Pinto DJ, Rossi KA, Myers JE Jr, Sheriff S, Lou Z, Zheng JJ, Harper TW, Bozarth JM, Wu Y, Luettgen JM, Seiffert DA, Decicco CP, Wexler RR, Quan ML J Med Chem. 2017 Feb 9;60(3):1060-1075. doi: 10.1021/acs.jmedchem.6b01460. Epub, 2017 Jan 31. PMID:28085275<ref>PMID:28085275</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5tkt" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Coagulation factor XIa]] | ||
[[Category: Sheriff, S]] | [[Category: Sheriff, S]] | ||
| + | [[Category: Blood coagulation factor]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
| + | [[Category: Protein inhibitor complex]] | ||
| + | [[Category: Serine protease]] | ||
Revision as of 09:41, 11 March 2017
FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((12E,15S)-15-(((2E)-3-(5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL)-2-PROPENOYL)AMINO)-9-OXO-8,17,19-TRIAZATRICYCLO[14.2.1.0~2,7~]NONADECA-1(18),2,4,6,12,16(19)-HEXAEN-5-YL)CARBAMATE
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