5qqo

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(New page: '''Unreleased structure''' The entry 5qqo is ON HOLD Authors: Sheriff, S. Description: FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((12E,15S)-15-(6-(3-CHLOROPHENYL)-2-OXO-1,3-OXAZI...)
Current revision (09:21, 23 October 2024) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 5qqo is ON HOLD
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==FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl [(5E,8S)-8-[(6R)-6-(3-chlorophenyl)-2-oxo-1,3-oxazinan-3-yl]-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl]carbamate==
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<StructureSection load='5qqo' size='340' side='right'caption='[[5qqo]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5qqo]] 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=5QQO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QQO 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&#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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NRJ:methyl+~{N}-[(12~{E},15~{S})-15-[(6~{R})-6-(3-chlorophenyl)-2-oxidanylidene-1,3-oxazinan-3-yl]-9-oxidanylidene-8,17,19-triazatricyclo[14.2.1.0^{2,7}]nonadeca-1(18),2,4,6,12,16(19)-hexaen-5-yl]carbamate'>NRJ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5qqo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qqo OCA], [https://pdbe.org/5qqo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qqo RCSB], [https://www.ebi.ac.uk/pdbsum/5qqo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qqo ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[https://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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[https://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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This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.
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Authors: Sheriff, S.
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Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.,Clark CG, Rossi KA, Corte JR, Fang T, Smallheer JM, De Lucca I, Nirschl DS, Orwat MJ, Pinto DJP, Hu Z, Wang Y, Yang W, Jeon Y, Ewing WR, Myers JE Jr, Sheriff S, Lou Z, Bozarth JM, Wu Y, Rendina A, Harper T, Zheng J, Xin B, Xiang Q, Luettgen JM, Seiffert DA, Wexler RR, Lam PYS Bioorg Med Chem Lett. 2019 Oct 1;29(19):126604. doi: 10.1016/j.bmcl.2019.08.008. , Epub 2019 Aug 16. PMID:31445854<ref>PMID:31445854</ref>
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Description: FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((12E,15S)-15-(6-(3-CHLOROPHENYL)-2-OXO-1,3-OXAZINAN-3-YL)-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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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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[[Category: Sheriff, S]]
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<div class="pdbe-citations 5qqo" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Factor XIa 3D structures|Factor XIa 3D structures]]
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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: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Sheriff S]]

Current revision

FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl [(5E,8S)-8-[(6R)-6-(3-chlorophenyl)-2-oxo-1,3-oxazinan-3-yl]-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl]carbamate

PDB ID 5qqo

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OCA

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