1cvw
From Proteopedia
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
| - | Factor VIIa (FVIIa) is a crucial haemostatic protease consisting of four | + | Factor VIIa (FVIIa) is a crucial haemostatic protease consisting of four distinct domains termed the Gla, epidermal growth factor-1 (EGF-1), EGF-2, and protease domains (from N- to C-terminus). The crystal structure of human FVIIa inhibited at the active site with 1, 5-dansyl-Glu-Gly-Arg-chloromethyl ketone and lacking the Gla domain has been solved to a resolution of 2.28 A. The EGF-2 and protease domains were well resolved, whereas no electron density for the EGF-1 domain was observed, suggesting a flexible arrangement or disorder within the crystal. Superposition of the protease domain of the present structure with that previously resolved in the tissue factor (TF)/FVIIai complex revealed that although overall the domain structures are similar, the EGF-2 domain is rotated by 7.5 degrees relative to the protease domain on binding TF. A single cleavage in the protease domain was found, between Arg315 and Lys316 (chymotrypsin numbering 170C-170D) in a FVII-specific insertion loop: this cleavage appeared to be essential for crystallisation. Insertion of the heavy chain N-terminal Ile153 is essentially identical in the two structures, as is the geometry of the active site residues and the inhibitor C-terminal arginine residue. Some differences are seen in the cleaved loop, but changes in TF-contact residues are generally minor. This structure supports the hypothesis that TF binding enables spatial domain arrangements in the flexible FVIIa molecule necessary for procoagulant function and furthermore that active site occupancy induces FVIIa active conformation via N-terminal insertion. |
==Disease== | ==Disease== | ||
| Line 18: | Line 18: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Harlos, K.]] | [[Category: Harlos, K.]] | ||
| - | [[Category: Johnson, D | + | [[Category: Johnson, D J.D.]] |
[[Category: Kemball-Cook, G.]] | [[Category: Kemball-Cook, G.]] | ||
| - | [[Category: Tuddenham, E | + | [[Category: Tuddenham, E G.D.]] |
[[Category: ANS]] | [[Category: ANS]] | ||
[[Category: CA]] | [[Category: CA]] | ||
| Line 30: | Line 30: | ||
[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:10:19 2008'' |
Revision as of 10:10, 21 February 2008
|
CRYSTAL STRUCTURE OF ACTIVE SITE-INHIBITED HUMAN COAGULATION FACTOR VIIA (DES-GLA)
Contents |
Overview
Factor VIIa (FVIIa) is a crucial haemostatic protease consisting of four distinct domains termed the Gla, epidermal growth factor-1 (EGF-1), EGF-2, and protease domains (from N- to C-terminus). The crystal structure of human FVIIa inhibited at the active site with 1, 5-dansyl-Glu-Gly-Arg-chloromethyl ketone and lacking the Gla domain has been solved to a resolution of 2.28 A. The EGF-2 and protease domains were well resolved, whereas no electron density for the EGF-1 domain was observed, suggesting a flexible arrangement or disorder within the crystal. Superposition of the protease domain of the present structure with that previously resolved in the tissue factor (TF)/FVIIai complex revealed that although overall the domain structures are similar, the EGF-2 domain is rotated by 7.5 degrees relative to the protease domain on binding TF. A single cleavage in the protease domain was found, between Arg315 and Lys316 (chymotrypsin numbering 170C-170D) in a FVII-specific insertion loop: this cleavage appeared to be essential for crystallisation. Insertion of the heavy chain N-terminal Ile153 is essentially identical in the two structures, as is the geometry of the active site residues and the inhibitor C-terminal arginine residue. Some differences are seen in the cleaved loop, but changes in TF-contact residues are generally minor. This structure supports the hypothesis that TF binding enables spatial domain arrangements in the flexible FVIIa molecule necessary for procoagulant function and furthermore that active site occupancy induces FVIIa active conformation via N-terminal insertion.
Disease
Known diseases associated with this structure: Factor VII deficiency OMIM:[227500], Myocardial infarction, decreased susceptibility to OMIM:[227500]
About this Structure
1CVW is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Coagulation factor VIIa, with EC number 3.4.21.21 Full crystallographic information is available from OCA.
Reference
Crystal structure of active site-inhibited human coagulation factor VIIa (des-Gla)., Kemball-Cook G, Johnson DJ, Tuddenham EG, Harlos K, J Struct Biol. 1999 Oct;127(3):213-23. PMID:10544046
Page seeded by OCA on Thu Feb 21 12:10:19 2008
