2a2q
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Complex of Active-site Inhibited Human Coagulation Factor VIIa with Human Soluble Tissue Factor in the Presence of Ca2+, Mg2+, Na+, and Zn2+
OverviewOverview
Factor VIIa (FVIIa) consists of a gamma-carboxyglutamic acid (Gla) domain, two epidermal growth factor-like domains, and a protease domain. FVIIa, binds seven Ca(2+) ions in the Gla, one in the EGF1, and one in the, protease domain. However, blood contains both Ca(2+) and Mg(2+), and the, Ca(2+) sites in FVIIa that could be specifically occupied by Mg(2+) are, unknown. Furthermore, FVIIa contains a Na(+) and two Zn(2+) sites, but, ligands for these cations are undefined. We obtained, p-aminobenzamidine-VIIa/soluble tissue factor (sTF) crystals under, conditions containing Ca(2+), Mg(2+), Na(+), and Zn(2+). The crystal, diffracted to 1.8A resolution, and the final structure has an R-factor of, 19.8%. In this structure, the Gla domain has four Ca(2+) and three bound, Mg(2+). The EGF1 domain contains one Ca(2+) site, and the protease domain, contains one Ca(2+), one Na(+), and two Zn(2+) sites. (45)Ca(2+) binding, in the presence/absence of Mg(2+) to FVIIa, Gla-domainless FVIIa, and, prothrombin fragment 1 supports the crystal data. Furthermore, unlike in, other serine proteases, the amide N of Gly(193) in FVIIa points away from, the oxyanion hole in this structure. Importantly, the oxyanion hole is, also absent in the benzamidine-FVIIa/sTF structure at 1.87A resolution., However, soaking benzamidine-FVIIa/sTF crystals with, d-Phe-Pro-Arg-chloromethyl ketone results in benzamidine displacement, d-Phe-Pro-Arg incorporation, and oxyanion hole formation by a flip of the, 192-193 peptide bond in FVIIa. Thus, it is the substrate and not the TF, binding that induces oxyanion hole formation and functional active site, geometry in FVIIa. Absence of oxyanion hole is unusual and has biologic, implications for FVIIa macromolecular substrate specificity and catalysis.
DiseaseDisease
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 StructureAbout this Structure
2A2Q is a Protein complex structure of sequences from Homo sapiens with GLC, FUC, MG, CA, NA, ZN, CL and PBZ as ligands. Active as Coagulation factor VIIa, with EC number 3.4.21.21 Full crystallographic information is available from OCA.
ReferenceReference
High resolution structures of p-aminobenzamidine- and benzamidine-VIIa/soluble tissue factor: unpredicted conformation of the 192-193 peptide bond and mapping of Ca2+, Mg2+, Na+, and Zn2+ sites in factor VIIa., Bajaj SP, Schmidt AE, Agah S, Bajaj MS, Padmanabhan K, J Biol Chem. 2006 Aug 25;281(34):24873-88. Epub 2006 Jun 6. PMID:16757484
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