2puq

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Revision as of 21:20, 12 November 2007

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spinqualitylabelsall models 2puq, resolution 2.050Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of active site inhibited coagulation factor VIIA in complex with soluble tissue factor

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The remarkably high specificity of the coagulation proteases towards, macromolecular substrates is provided by numerous interactions involving, the catalytic groove and remote exosites. For factor VIIa (FVIIa), the, principal initiator of coagulation via the extrinsic pathway, several, exosites have been identified, whereas only little is known about the, specificity dictated by the active-site architecture. Here, we have, profiled the primary P4-P1 substrate specificity of FVIIa using positional, scanning-substrate combinatorial libraries and evaluated the role of, selective active site in defining specificity. Being a trypsin-like serine, protease, FVIIa showed P1 specificity exclusively towards Arg and Lys. In, the S2 pocket Thr, Leu, Phe and Val were the most preferred amino acids., Both S3 and S4 appeared to be rather promiscuous, however, with some, preference for aromatic amino acids at both positions. Interestingly, a, significant degree of interdependence between the S3 and S4 was observed, and as a consequence, the optimal substrate for FVIIa could not be derived, directly from a sub-site directed specificity screen. To evaluate the role, of the active site residues in defining specificity, a series of mutants, of FVIIa were prepared at position 239 (c99), which is considered one of, the most important residues for determining P2 specificity of the trypsin, family members. This was confirmed for FVIIa by marked changes in primary, substrate specificity and reduced rates of antithrombin III inhibition., Interestingly, these changes do not necessarily coincide with an altered, ability to activate factor X demonstrating that inhibitor and, macromolecular substrate selectivity may be engineered separately.

Disease

Known diseases associated with this structure: Esophageal squamous cell carcinoma OMIM:[606551], Factor VII deficiency OMIM:[227500], Myocardial infarction, decreased susceptibility to OMIM:[227500]

About this Structure

2PUQ is a Protein complex structure of sequences from Homo sapiens with GLC, FUC, CA and CH2 as ligands. This structure superseeds the now removed PDB entry 2PMM. Active as Coagulation factor VIIa, with EC number 3.4.21.21 Full crystallographic information is available from OCA.

Reference

Engineering the substrate and inhibitor specificities of human coagulation factor VIIa., Larsen KS, Ostergaard H, Bjelke JR, Olsen OH, Rasmussen HB, Christensen L, Kragelund BB, Stennicke HR, Biochem J. 2007 Apr 25;. PMID:17456045

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