1xxf
From Proteopedia
(New page: 200px<br /> <applet load="1xxf" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xxf, resolution 2.60Å" /> '''Crystal Structure o...) |
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| - | [[Image:1xxf.gif|left|200px]]<br /> | + | [[Image:1xxf.gif|left|200px]]<br /><applet load="1xxf" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1xxf" size=" | + | |
caption="1xxf, resolution 2.60Å" /> | caption="1xxf, resolution 2.60Å" /> | ||
'''Crystal Structure of the FXIa Catalytic Domain in Complex with Ecotin Mutant (EcotinP)'''<br /> | '''Crystal Structure of the FXIa Catalytic Domain in Complex with Ecotin Mutant (EcotinP)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Thrombosis can lead to life-threatening conditions such as acute | + | Thrombosis can lead to life-threatening conditions such as acute myocardial infarction, pulmonary embolism, and stroke. Although commonly used anti-coagulant drugs, such as low molecular weight heparin and warfarin, are effective, they carry a significant risk of inducing severe bleeding complications, and there is a need for safer drugs. Activated Factor XI (FXIa) is a key enzyme in the amplification phase of the coagulation cascade. Anti-human FXI antibody significantly reduces thrombus growth in a baboon thrombosis model without bleeding problems (Gruber, A., and Hanson, S. R. (2003) Blood 102, 953-955). Therefore, FXIa is a potential target for anti-thrombosis therapy. To determine the structure of FXIa, we derived a recombinant catalytic domain of FXI, consisting of residues 370-607 (rhFXI370-607). Here we report the first crystal structure of rhFXI370-607 in complex with a substitution mutant of ecotin, a panserine protease protein inhibitor secreted by Escherichia coli, to 2.2 A resolution. The presence of ecotin not only assisted in the crystallization of the enzyme but also revealed unique structural features in the active site of FXIa. Subsequently, the sequence from P5 to P2' in ecotin was mutated to the FXIa substrate sequence, and the structures of the rhFXI370-607-ecotin mutant complexes were determined. These structures provide us with an understanding of substrate binding interactions of FXIa, the structural information essential for the structure-based design of FXIa-selective inhibitors. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XXF is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NA 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:// | + | 1XXF is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NA:'>NA</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=1XXF OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Abdel-Meguid, S | + | [[Category: Abdel-Meguid, S S.]] |
| - | [[Category: Babine, R | + | [[Category: Babine, R E.]] |
[[Category: Gelfand, E.]] | [[Category: Gelfand, E.]] | ||
| - | [[Category: Gorga, J | + | [[Category: Gorga, J C.]] |
[[Category: Jin, L.]] | [[Category: Jin, L.]] | ||
[[Category: Pandey, P.]] | [[Category: Pandey, P.]] | ||
| - | [[Category: Seidl, K | + | [[Category: Seidl, K J.]] |
| - | [[Category: Strickler, J | + | [[Category: Strickler, J E.]] |
| - | [[Category: Weaver, D | + | [[Category: Weaver, D T.]] |
[[Category: NA]] | [[Category: NA]] | ||
[[Category: fxia; catalytic domain; serine protease; ecotin; substrate-like interaction]] | [[Category: fxia; catalytic domain; serine protease; ecotin; substrate-like interaction]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:59:41 2008'' |
Revision as of 13:59, 21 February 2008
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Crystal Structure of the FXIa Catalytic Domain in Complex with Ecotin Mutant (EcotinP)
Contents |
Overview
Thrombosis can lead to life-threatening conditions such as acute myocardial infarction, pulmonary embolism, and stroke. Although commonly used anti-coagulant drugs, such as low molecular weight heparin and warfarin, are effective, they carry a significant risk of inducing severe bleeding complications, and there is a need for safer drugs. Activated Factor XI (FXIa) is a key enzyme in the amplification phase of the coagulation cascade. Anti-human FXI antibody significantly reduces thrombus growth in a baboon thrombosis model without bleeding problems (Gruber, A., and Hanson, S. R. (2003) Blood 102, 953-955). Therefore, FXIa is a potential target for anti-thrombosis therapy. To determine the structure of FXIa, we derived a recombinant catalytic domain of FXI, consisting of residues 370-607 (rhFXI370-607). Here we report the first crystal structure of rhFXI370-607 in complex with a substitution mutant of ecotin, a panserine protease protein inhibitor secreted by Escherichia coli, to 2.2 A resolution. The presence of ecotin not only assisted in the crystallization of the enzyme but also revealed unique structural features in the active site of FXIa. Subsequently, the sequence from P5 to P2' in ecotin was mutated to the FXIa substrate sequence, and the structures of the rhFXI370-607-ecotin mutant complexes were determined. These structures provide us with an understanding of substrate binding interactions of FXIa, the structural information essential for the structure-based design of FXIa-selective 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
1XXF is a Protein complex structure of sequences from Escherichia coli and 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
Crystal structures of the FXIa catalytic domain in complex with ecotin mutants reveal substrate-like interactions., Jin L, Pandey P, Babine RE, Gorga JC, Seidl KJ, Gelfand E, Weaver DT, Abdel-Meguid SS, Strickler JE, J Biol Chem. 2005 Feb 11;280(6):4704-12. Epub 2004 Nov 15. PMID:15545266
Page seeded by OCA on Thu Feb 21 15:59:41 2008
Categories: Coagulation factor XIa | Escherichia coli | Homo sapiens | Protein complex | Abdel-Meguid, S S. | Babine, R E. | Gelfand, E. | Gorga, J C. | Jin, L. | Pandey, P. | Seidl, K J. | Strickler, J E. | Weaver, D T. | NA | Fxia; catalytic domain; serine protease; ecotin; substrate-like interaction
