8bo6

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'''Unreleased structure'''
 
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The entry 8bo6 is ON HOLD until Paper Publication
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==COAGULATION FACTOR XI PROTEASE DOMAIN IN COMPLEX WITH ACTIVE SITE INHIBITOR 2==
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<StructureSection load='8bo6' size='340' side='right'caption='[[8bo6]], [[Resolution|resolution]] 1.25&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[8bo6]] 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=8BO6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BO6 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]] 1.25&#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=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=QW0:(~{E})-~{N}-[[5-(3-azanyl-1~{H}-indazol-6-yl)-4-chloranyl-1~{H}-imidazol-2-yl]methyl]-3-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enamide'>QW0</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=8bo6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bo6 OCA], [https://pdbe.org/8bo6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bo6 RCSB], [https://www.ebi.ac.uk/pdbsum/8bo6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bo6 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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Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.
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Authors: Schaefer, M., Roehrig, S., Ackerstaff, J., Nunez, E.J., Gericke, K.M., Meier, K., Tersteegen, A., Stampfuss, J., Ellerbrock, P., Meibom, D., Lang, D., Heitmeier, S., Hillisch, A.
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Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.,Roehrig S, Ackerstaff J, Jimenez Nunez E, Teller H, Ellerbrock P, Meier K, Heitmeier S, Tersteegen A, Stampfuss J, Lang D, Schlemmer KH, Schaefer M, Gericke KM, Kinzel T, Meibom D, Schmidt M, Gerdes C, Follmann M, Hillisch A J Med Chem. 2023 Sep 14;66(17):12203-12224. doi: 10.1021/acs.jmedchem.3c00795. , Epub 2023 Sep 5. PMID:37669040<ref>PMID:37669040</ref>
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Description: COAGULATION FACTOR XI PROTEASE DOMAIN IN COMPLEX WITH ACTIVE SITE INHIBITOR 2
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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: Ellerbrock, P]]
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<div class="pdbe-citations 8bo6" style="background-color:#fffaf0;"></div>
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[[Category: Hillisch, A]]
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== References ==
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[[Category: Gericke, K.M]]
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<references/>
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[[Category: Ackerstaff, J]]
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__TOC__
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[[Category: Nunez, E.J]]
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</StructureSection>
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[[Category: Heitmeier, S]]
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[[Category: Homo sapiens]]
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[[Category: Meier, K]]
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[[Category: Large Structures]]
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[[Category: Lang, D]]
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[[Category: Ackerstaff J]]
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[[Category: Stampfuss, J]]
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[[Category: Ellerbrock P]]
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[[Category: Schaefer, M]]
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[[Category: Gericke KM]]
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[[Category: Roehrig, S]]
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[[Category: Heitmeier S]]
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[[Category: Tersteegen, A]]
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[[Category: Hillisch A]]
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[[Category: Meibom, D]]
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[[Category: Lang D]]
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[[Category: Meibom D]]
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[[Category: Meier K]]
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[[Category: Nunez EJ]]
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[[Category: Roehrig S]]
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[[Category: Schaefer M]]
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[[Category: Stampfuss J]]
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[[Category: Tersteegen A]]

Revision as of 18:12, 20 September 2023

COAGULATION FACTOR XI PROTEASE DOMAIN IN COMPLEX WITH ACTIVE SITE INHIBITOR 2

PDB ID 8bo6

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