1fjs

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(New page: 200px<br /> <applet load="1fjs" size="450" color="white" frame="true" align="right" spinBox="true" caption="1fjs, resolution 1.92&Aring;" /> '''CRYSTAL STRUCTURE O...)
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[[Image:1fjs.gif|left|200px]]<br />
 
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<applet load="1fjs" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1fjs, resolution 1.92&Aring;" />
 
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'''CRYSTAL STRUCTURE OF THE INHIBITOR ZK-807834 (CI-1031) COMPLEXED WITH FACTOR XA'''<br />
 
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==Overview==
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==CRYSTAL STRUCTURE OF THE INHIBITOR ZK-807834 (CI-1031) COMPLEXED WITH FACTOR XA==
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Factor Xa plays a critical role in the formation of blood clots. This, serine protease catalyzes the conversion of prothrombin to thrombin, the, first joint step that links the intrinsic and extrinsic coagulation, pathways. There is considerable interest in the development of factor Xa, inhibitors for the intervention in thrombic diseases. This paper presents, the structure of the inhibitor ZK-807834, also known as CI-1031, bound to, factor Xa and provides the details of the protein purification and, crystallization. Results from mass spectrometry indicate that the factor, Xa underwent autolysis during crystallization and the first EGF-like, domain was cleaved from the protein. The crystal structure of the complex, shows that the amidine of ZK-807834 forms a salt bridge with Asp189 in the, S1 pocket and the basic imidazoline fits snugly into the S4 site. The, central pyridine ring provides a fairly rigid linker between these groups., This rigidity helps minimize entropic losses during binding. In addition, the structure reveals new interactions that were not found in the previous, factor Xa/inhibitor complexes. ZK-807834 forms a strong hydrogen bond, between an ionized 2-hydroxy group and Ser195 of factor Xa. There is also, an aromatic ring-stacking interaction between the inhibitor and Trp215 in, the S4 pocket. These interactions contribute to both the potency of this, compound (K(I) = 0.11 nM) and the &gt;2500-fold selectivity against, homologous serine proteases such as trypsin.
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<StructureSection load='1fjs' size='340' side='right'caption='[[1fjs]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1fjs]] 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=1FJS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FJS 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]] 1.92&#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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=Z34:N-[2-[5-[AMINO(IMINO)METHYL]-2-HYDROXYPHENOXY]-3,5-DIFLUORO-6-[3-(4,5-DIHYDRO-1-METHYL-1H-IMIDAZOL-2-YL)PHENOXY]PYRIDIN-4-YL]-N-METHYLGLYCINE'>Z34</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=1fjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fjs OCA], [https://pdbe.org/1fjs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fjs RCSB], [https://www.ebi.ac.uk/pdbsum/1fjs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fjs 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/fj/1fjs_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=1fjs 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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Factor Xa plays a critical role in the formation of blood clots. This serine protease catalyzes the conversion of prothrombin to thrombin, the first joint step that links the intrinsic and extrinsic coagulation pathways. There is considerable interest in the development of factor Xa inhibitors for the intervention in thrombic diseases. This paper presents the structure of the inhibitor ZK-807834, also known as CI-1031, bound to factor Xa and provides the details of the protein purification and crystallization. Results from mass spectrometry indicate that the factor Xa underwent autolysis during crystallization and the first EGF-like domain was cleaved from the protein. The crystal structure of the complex shows that the amidine of ZK-807834 forms a salt bridge with Asp189 in the S1 pocket and the basic imidazoline fits snugly into the S4 site. The central pyridine ring provides a fairly rigid linker between these groups. This rigidity helps minimize entropic losses during binding. In addition, the structure reveals new interactions that were not found in the previous factor Xa/inhibitor complexes. ZK-807834 forms a strong hydrogen bond between an ionized 2-hydroxy group and Ser195 of factor Xa. There is also an aromatic ring-stacking interaction between the inhibitor and Trp215 in the S4 pocket. These interactions contribute to both the potency of this compound (K(I) = 0.11 nM) and the &gt;2500-fold selectivity against homologous serine proteases such as trypsin.
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==Disease==
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Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa.,Adler M, Davey DD, Phillips GB, Kim SH, Jancarik J, Rumennik G, Light DR, Whitlow M Biochemistry. 2000 Oct 17;39(41):12534-42. PMID:11027132<ref>PMID:11027132</ref>
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Known disease associated with this structure: Factor X deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227600 227600]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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1FJS is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA, CL, Z34 and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1FJS OCA].
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</div>
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<div class="pdbe-citations 1fjs" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa., Adler M, Davey DD, Phillips GB, Kim SH, Jancarik J, Rumennik G, Light DR, Whitlow M, Biochemistry. 2000 Oct 17;39(41):12534-42. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11027132 11027132]
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*[[Factor Xa|Factor Xa]]
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[[Category: Coagulation factor Xa]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
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[[Category: Adler, M.]]
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[[Category: Adler M]]
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[[Category: Whitlow, M.]]
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[[Category: Whitlow M]]
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[[Category: CA]]
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[[Category: CL]]
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[[Category: GOL]]
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[[Category: Z34]]
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[[Category: coagulation cofactor]]
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[[Category: protease]]
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[[Category: protein inhibitor complex]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:53:57 2007''
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Current revision

CRYSTAL STRUCTURE OF THE INHIBITOR ZK-807834 (CI-1031) COMPLEXED WITH FACTOR XA

PDB ID 1fjs

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