3k9x

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[[Image:3k9x.png|left|200px]]
 
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{{STRUCTURE_3k9x| PDB=3k9x | SCENE= }}
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==X-ray crystal structure of human fxa in complex with (S)-N-((2-METHYLBENZOFURAN-5-YLAMINO)(2-OXO-1-(2-OXO-2- (PYRROLIDIN-1-YL)ETHYL)AZEPAN-3- YLAMINO)METHYLENE)NICOTINAMIDE==
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<StructureSection load='3k9x' size='340' side='right'caption='[[3k9x]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3k9x]] is a 4 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=3K9X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3K9X 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]] 1.9&#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=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MBM:N-{N-(2-METHYL-1-BENZOFURAN-5-YL)-N-[(3S)-2-OXO-1-(2-OXO-2-PYRROLIDIN-1-YLETHYL)AZEPAN-3-YL]CARBAMIMIDOYL}PYRIDINE-3-CARBOXAMIDE'>MBM</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=3k9x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k9x OCA], [https://pdbe.org/3k9x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3k9x RCSB], [https://www.ebi.ac.uk/pdbsum/3k9x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3k9x ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[https://omim.org/entry/227600 227600]. A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis.<ref>PMID:2790181</ref> <ref>PMID:1973167</ref> <ref>PMID:1985698</ref> <ref>PMID:7669671</ref> <ref>PMID:8529633</ref> <ref>PMID:7860069</ref> <ref>PMID:8845463</ref> <ref>PMID:8910490</ref> <ref>PMID:10468877</ref> <ref>PMID:10746568</ref> <ref>PMID:10739379</ref> <ref>PMID:11248282</ref> <ref>PMID:11728527</ref> <ref>PMID:12945883</ref> <ref>PMID:15650540</ref> <ref>PMID:17393015</ref> <ref>PMID:19135706</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k9/3k9x_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3k9x ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
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===X-ray crystal structure of human fxa in complex with (S)-N-((2-METHYLBENZOFURAN-5-YLAMINO)(2-OXO-1-(2-OXO-2- (PYRROLIDIN-1-YL)ETHYL)AZEPAN-3- YLAMINO)METHYLENE)NICOTINAMIDE===
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Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577.,Shi Y, Li C, O'Connor SP, Zhang J, Shi M, Bisaha SN, Wang Y, Sitkoff D, Pudzianowski AT, Huang C, Klei HE, Kish K, Yanchunas J Jr, Liu EC, Hartl KS, Seiler SM, Steinbacher TE, Schumacher WA, Atwal KS, Stein PD Bioorg Med Chem Lett. 2009 Dec 15;19(24):6882-9. Epub 2009 Oct 23. PMID:19896847<ref>PMID:19896847</ref>
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{{ABSTRACT_PUBMED_19896847}}
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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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==About this Structure==
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<div class="pdbe-citations 3k9x" style="background-color:#fffaf0;"></div>
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[[3k9x]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3K9X OCA].
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==See Also==
==See Also==
*[[Factor Xa|Factor Xa]]
*[[Factor Xa|Factor Xa]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:019896847</ref><references group="xtra"/>
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__TOC__
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[[Category: Coagulation factor Xa]]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Ghosh, K.]]
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[[Category: Large Structures]]
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[[Category: Kish, K.]]
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[[Category: Ghosh K]]
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[[Category: Klei, H E.]]
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[[Category: Kish K]]
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[[Category: Rushith, A.]]
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[[Category: Klei HE]]
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[[Category: Blood clotting]]
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[[Category: Rushith A]]
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[[Category: Blood coagulation]]
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[[Category: Blood coagulation factor]]
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[[Category: Cleavage on pair of basic residue]]
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[[Category: Disulfide bond]]
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[[Category: Egf-like domain]]
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[[Category: Epidermal growth factor like domain]]
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[[Category: Gamma-carboxyglutamic acid]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Hydroxylation]]
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[[Category: Protease]]
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[[Category: Secreted]]
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[[Category: Serine protease]]
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[[Category: Zymogen]]
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Current revision

X-ray crystal structure of human fxa in complex with (S)-N-((2-METHYLBENZOFURAN-5-YLAMINO)(2-OXO-1-(2-OXO-2- (PYRROLIDIN-1-YL)ETHYL)AZEPAN-3- YLAMINO)METHYLENE)NICOTINAMIDE

PDB ID 3k9x

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