4ibl

Rubidium Sites in Blood Coagulation Factor VIIa

spinqualitylabelsall models 4ibl, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ibl is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: BEN, BGC, CA, CGU, CL, FUC, MG, RB Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease FA7_HUMAN Defects in F7 are the cause of factor VII deficiency (FA7D) [MIM:227500. A hemorrhagic disease with variable presentation. The clinical picture can be very severe, with the early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, moderate with cutaneous-mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by a surgical intervention. Finally, numerous subjects are completely asymptomatic despite very low factor VII levels. Function FA7_HUMAN Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium. Publication Abstract from PubMed Coagulation factor VIIa (FVIIa) consists of a gamma-carboxyglutamic acid (GLA) domain, two epidermal growth factor-like (EGF) domains and a protease domain. FVIIa binds three Mg(2+) ions and four Ca(2+) ions in the GLA domain, one Ca(2+) ion in the EGF1 domain and one Ca(2+) ion in the protease domain. Further, FVIIa contains an Na(+) site in the protease domain. Since Na(+) and water share the same number of electrons, Na(+) sites in proteins are difficult to distinguish from waters in X-ray structures. Here, to verify the Na(+) site in FVIIa, the structure of the FVIIa-soluble tissue factor (TF) complex was solved at 1.8 A resolution containing Mg(2+), Ca(2+) and Rb(+) ions. In this structure, Rb(+) replaced two Ca(2+) sites in the GLA domain and occupied three non-metal sites in the protease domain. However, Rb(+) was not detected at the expected Na(+) site. In kinetic experiments, Na(+) increased the amidolytic activity of FVIIa towards the synthetic substrate S-2288 (H-D-Ile-Pro-Arg-p-nitroanilide) by approximately 20-fold; however, in the presence of Ca(2+), Na(+) had a negligible effect. Ca(2+) increased the hydrolytic activity of FVIIa towards S-2288 by approximately 60-fold in the absence of Na(+) and by approximately 82-fold in the presence of Na(+). In molecular-dynamics simulations, Na(+) stabilized the two Na(+)-binding loops (the 184-loop and 220-loop) and the TF-binding region spanning residues 163-180. Ca(2+) stabilized the Ca(2+)-binding loop (the 70-loop) and Na(+)-binding loops but not the TF-binding region. Na(+) and Ca(2+) together stabilized both the Na(+)-binding and Ca(2+)-binding loops and the TF-binding region. Previously, Rb(+) has been used to define the Na(+) site in thrombin; however, it was unsuccessful in detecting the Na(+) site in FVIIa. A conceivable explanation for this observation is provided. Structure of human factor VIIa-soluble tissue factor with calcium, magnesium and rubidium.,Vadivel K, Schmidt AE, Cascio D, Padmanabhan K, Krishnaswamy S, Brandstetter H, Bajaj SP Acta Crystallogr D Struct Biol. 2021 Jun 1;77(Pt 6):809-819. doi:, 10.1107/S2059798321003922. Epub 2021 May 14. PMID:34076594 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Factor VIIa 3D structures Tissue factor

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