1zhr: Difference between revisions

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-[[Image:1zhr.gif|left|200px]]<br />
-<applet load="1zhr" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1zhr, resolution 1.73&Aring;" />
-'''Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-C482S-K437A Mutant)'''<br />
-==Overview==
+==Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-C482S-K437A Mutant)==
-Activated factor XI (FXIa) is a key enzyme in the amplification phase of, the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have, lesser bleeding liabilities and provide a safe alternative for, antithrombosis therapy to available drugs on the market. In a previous, report, the crystal structures of the catalytic domain of FXIa, (rhFXI(370-607)) in complex with various ecotin mutants have been, described. However, ecotin forms a matrix-like interaction with, rhFXI(370-607) and is impossible to displace with small-molecule, inhibitors; ecotin crystals are therefore not suitable for iterative, structure-based ligand design. In addition, rhFXI(370-607) did not, crystallize in the presence of small-molecule ligands. In order to obtain, the crystal structure of rhFXI(370-607) with a weak small-molecule ligand, namely benzamidine, several rounds of surface-residue mutation were, implemented to promote crystal formation of rhFXI(370-607). A quadruple, mutant of rhFXI(370-607) (rhFXI(370-607)-S434A,T475A,C482S,K437A) readily, crystallized in the presence of benzamidine. The benzamidine in the, preformed crystals was easily exchanged with other FXIa small-molecule, inhibitors. These crystals have facilitated the structure-based design of, small-molecule FXIa inhibitors.
+<StructureSection load='1zhr' size='340' side='right'caption='[[1zhr]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1zhr]] 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=1ZHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ZHR FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.73&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BEN:BENZAMIDINE'>BEN</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1zhr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zhr OCA], [https://pdbe.org/1zhr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1zhr RCSB], [https://www.ebi.ac.uk/pdbsum/1zhr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1zhr ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[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 ==
+[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.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zh/1zhr_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=1zhr ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Activated factor XI (FXIa) is a key enzyme in the amplification phase of the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have lesser bleeding liabilities and provide a safe alternative for antithrombosis therapy to available drugs on the market. In a previous report, the crystal structures of the catalytic domain of FXIa (rhFXI(370-607)) in complex with various ecotin mutants have been described. However, ecotin forms a matrix-like interaction with rhFXI(370-607) and is impossible to displace with small-molecule inhibitors; ecotin crystals are therefore not suitable for iterative structure-based ligand design. In addition, rhFXI(370-607) did not crystallize in the presence of small-molecule ligands. In order to obtain the crystal structure of rhFXI(370-607) with a weak small-molecule ligand, namely benzamidine, several rounds of surface-residue mutation were implemented to promote crystal formation of rhFXI(370-607). A quadruple mutant of rhFXI(370-607) (rhFXI(370-607)-S434A,T475A,C482S,K437A) readily crystallized in the presence of benzamidine. The benzamidine in the preformed crystals was easily exchanged with other FXIa small-molecule inhibitors. These crystals have facilitated the structure-based design of small-molecule FXIa inhibitors.
-==Disease==
+Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors.,Jin L, Pandey P, Babine RE, Weaver DT, Abdel-Meguid SS, Strickler JE Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1418-25. Epub 2005, Sep 28. PMID:16204896<ref>PMID:16204896</ref>
-Known diseases associated with this structure: Factor XI deficiency, autosomal dominant OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=264900 264900]], Factor XI deficiency, autosomal recessive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=264900 264900]]
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-ZHR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with BEN as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1ZHR OCA].
+</div>
+<div class="pdbe-citations 1zhr" style="background-color:#fffaf0;"></div>
-==Reference==
+==See Also==
-Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors., Jin L, Pandey P, Babine RE, Weaver DT, Abdel-Meguid SS, Strickler JE, Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1418-25. Epub 2005, Sep 28. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16204896 16204896]
+*[[Factor XIa 3D structures|Factor XIa 3D structures]]
-[[Category: Coagulation factor XIa]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Abdel-Meguid, S.S.]]
+[[Category: Abdel-Meguid SS]]
-[[Category: Babine, R.E.]]
+[[Category: Babine RE]]
-[[Category: Jin, L.]]
+[[Category: Jin L]]
-[[Category: Pandey, P.]]
+[[Category: Pandey P]]
-[[Category: Strickler, J.E.]]
+[[Category: Strickler JE]]
-[[Category: Weaver, D.T.]]
+[[Category: Weaver DT]]
-[[Category: BEN]]
-[[Category: factor xi; benzamidine]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:34:41 2007''