4y8x

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'''Unreleased structure'''
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==Factor XIa in complex with the inhibitor methyl (4-{4-chloro-2-[(1S)-1-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate==
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<StructureSection load='4y8x' size='340' side='right' caption='[[4y8x]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4y8x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y8X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y8X 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=4GR:METHYL+(4-{4-CHLORO-2-[(1S)-1-({(2E)-3-[5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL]PROP-2-ENOYL}AMINO)-2-PHENYLETHYL]-1H-IMIDAZOL-5-YL}PHENYL)CARBAMATE'>4GR</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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">[[4y8y|4y8y]], [[4y8z|4y8z]]</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4y8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y8x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4y8x RCSB], [http://www.ebi.ac.uk/pdbsum/4y8x PDBsum]</span></td></tr>
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</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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Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7nM and modest oral exposure in dogs.
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The entry 4y8x is ON HOLD until Paper Publication
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Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.,Pinto DJ, Smallheer JM, Corte JR, Austin EJ, Wang C, Fang T, Smith LM 2nd, Rossi KA, Rendina AR, Bozarth JM, Zhang G, Wei A, Ramamurthy V, Sheriff S, Myers JE Jr, Morin PE, Luettgen JM, Seiffert DA, Quan ML, Wexler RR Bioorg Med Chem Lett. 2015 Feb 4. pii: S0960-894X(15)00040-2. doi:, 10.1016/j.bmcl.2015.01.028. PMID:25728130<ref>PMID:25728130</ref>
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Authors: Sheriff, S.
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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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Description: Factor XIa in complex with the inhibitor methyl (4-{4-chloro-2-[(1S)-1-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate
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== References ==
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[[Category: Unreleased Structures]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Coagulation factor XIa]]
[[Category: Sheriff, S]]
[[Category: Sheriff, S]]
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[[Category: Blood coagulation factor]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Protein inhibitor complex]]
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[[Category: Serine protease]]

Revision as of 15:52, 27 May 2015

Factor XIa in complex with the inhibitor methyl (4-{4-chloro-2-[(1S)-1-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate

4y8x, resolution 1.90Å

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