5exm

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'''Unreleased structure'''
 
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The entry 5exm is ON HOLD until Paper Publication
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==FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl ~{N}-[4-[2-[(1~{S})-1-[[4-(aminomethyl)cyclohexyl]carbonylamino]-2-phenyl-ethyl]pyridin-4-yl]phenyl]carbamate==
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<StructureSection load='5exm' size='340' side='right' caption='[[5exm]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5exm]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EXM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EXM 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=5ST:METHYL+~{N}-[4-[2-[(1~{S})-1-[[4-(AMINOMETHYL)CYCLOHEXYL]CARBONYLAMINO]-2-PHENYL-ETHYL]PYRIDIN-4-YL]PHENYL]CARBAMATE'>5ST</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">[[5exl|5exl]], [[5exn|5exn]]</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=5exm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5exm OCA], [http://pdbe.org/5exm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5exm RCSB], [http://www.ebi.ac.uk/pdbsum/5exm 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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Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.
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Authors: Wei, A.
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Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.,Corte JR, Fang T, Pinto DJ, Orwat MJ, Rendina AR, Luettgen JM, Rossi KA, Wei A, Ramamurthy V, Myers JE Jr, Sheriff S, Narayanan R, Harper TW, Zheng JJ, Li YX, Seiffert DA, Wexler RR, Quan ML Bioorg Med Chem. 2016 May 15;24(10):2257-72. doi: 10.1016/j.bmc.2016.03.062. Epub, 2016 Apr 1. PMID:27073051<ref>PMID:27073051</ref>
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Description: FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl ~{N}-[4-[2-[(1~{S})-1-[[4-(aminomethyl)cyclohexyl]carbonylamino]-2-phenyl-ethyl]pyridin-4-yl]phenyl]carbamate
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 5exm" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Coagulation factor XIa]]
[[Category: Wei, A]]
[[Category: Wei, A]]
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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 17:34, 10 May 2016

FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl ~{N}-[4-[2-[(1~{S})-1-[[4-(aminomethyl)cyclohexyl]carbonylamino]-2-phenyl-ethyl]pyridin-4-yl]phenyl]carbamate

5exm, resolution 2.09Å

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