4x6o

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==FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl (4-{4-chloro-2-[(1S)-1-({3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]propanoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate==
==FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl (4-{4-chloro-2-[(1S)-1-({3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]propanoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate==
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<StructureSection load='4x6o' size='340' side='right' caption='[[4x6o]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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<StructureSection load='4x6o' size='340' side='right'caption='[[4x6o]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4x6o]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X6O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X6O FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4x6o]] is a 1 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=4X6O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X6O 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=3Y4:METHYL+(4-{4-CHLORO-2-[(1S)-1-({3-[5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL]PROPANOYL}AMINO)-2-PHENYLETHYL]-1H-IMIDAZOL-5-YL}PHENYL)CARBAMATE'>3Y4</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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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]] 2.1&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4x6m|4x6m]], [[4x6n|4x6n]], [[4x6p|4x6p]]</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=3Y4:METHYL+(4-{4-CHLORO-2-[(1S)-1-({3-[5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL]PROPANOYL}AMINO)-2-PHENYLETHYL]-1H-IMIDAZOL-5-YL}PHENYL)CARBAMATE'>3Y4</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='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'>[https://proteopedia.org/fgij/fg.htm?mol=4x6o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x6o OCA], [https://pdbe.org/4x6o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x6o RCSB], [https://www.ebi.ac.uk/pdbsum/4x6o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x6o ProSAT]</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=4x6o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x6o OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4x6o RCSB], [http://www.ebi.ac.uk/pdbsum/4x6o PDBsum]</span></td></tr>
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</table>
</table>
== Disease ==
== 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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[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>
== Function ==
== 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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[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.
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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The structure-activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (+/-)-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between imidazole and six-membered ring analogs.
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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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Pyridine and pyridinone-based factor XIa inhibitors.,Corte JR, Fang T, Hangeland JJ, Friends TJ, Rendina AR, Luettgen JM, Bozarth JM, Barbera FA, Rossi KA, Wei A, Ramamurthy V, Morin PE, Seiffert DA, Wexler RR, Quan ML Bioorg Med Chem Lett. 2014 Dec 31. pii: S0960-894X(14)01358-4. doi:, 10.1016/j.bmcl.2014.12.050. PMID:25592713<ref>PMID:25592713</ref>
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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>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
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<div class="pdbe-citations 4x6o" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Factor XIa 3D structures|Factor XIa 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Coagulation factor XIa]]
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[[Category: Homo sapiens]]
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[[Category: Wei, A]]
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[[Category: Large Structures]]
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[[Category: Blood coagulation factor]]
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[[Category: Wei A]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Protein inhibitor complex]]
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[[Category: Serine protease]]
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Current revision

FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl (4-{4-chloro-2-[(1S)-1-({3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]propanoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate

PDB ID 4x6o

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