1zhr
From Proteopedia
(New page: 200px<br /> <applet load="1zhr" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zhr, resolution 1.73Å" /> '''Crystal Structure o...) |
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caption="1zhr, resolution 1.73Å" /> | caption="1zhr, resolution 1.73Å" /> | ||
'''Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-C482S-K437A Mutant)'''<br /> | '''Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-C482S-K437A Mutant)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Activated factor XI (FXIa) is a key enzyme in the amplification phase of | + | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1ZHR 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:// | + | 1ZHR 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 <scene name='pdbligand=BEN:'>BEN</scene> 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://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZHR OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Abdel-Meguid, S | + | [[Category: Abdel-Meguid, S S.]] |
| - | [[Category: Babine, R | + | [[Category: Babine, R E.]] |
[[Category: Jin, L.]] | [[Category: Jin, L.]] | ||
[[Category: Pandey, P.]] | [[Category: Pandey, P.]] | ||
| - | [[Category: Strickler, J | + | [[Category: Strickler, J E.]] |
| - | [[Category: Weaver, D | + | [[Category: Weaver, D T.]] |
[[Category: BEN]] | [[Category: BEN]] | ||
[[Category: factor xi; benzamidine]] | [[Category: factor xi; benzamidine]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:15:40 2008'' |
Revision as of 14:15, 21 February 2008
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Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Benzamidine (S434A-T475A-C482S-K437A Mutant)
Contents |
Overview
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
Known diseases associated with this structure: Factor XI deficiency, autosomal dominant OMIM:[264900], Factor XI deficiency, autosomal recessive OMIM:[264900]
About this Structure
1ZHR is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Coagulation factor XIa, with EC number 3.4.21.27 Full crystallographic information is available from OCA.
Reference
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
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