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Blood, Vol. 111, Issue 7, 3468-3478, April 1, 2008
Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites
Blood Venceslá et al.
111: 3468
Supplemental materials for: Vencesla et al
Files in this Data Supplement:
- Table S2. Structural impact of mutated residues on topological equivalent positions of homologous structures (PDF, 48.4 KB) -
The stability of hypothetical point mutants of bovine FVai and human ceruloplasmin (PDB codes 1SDD and 1KCW, respectively) corresponding to the novel FVIII missense mutations identified in this work was assessed with CUPSAT. For residues of the FV-A2 domain, the corresponding values for topologically equivalent residues in A1 and A3 domains are given. Mutations are classified as fold-stabilizing (S) or destabilizing (D), and the torsion angles as favorable (F) or unfavorable (U). Unless otherwise indicated, values for  G apply to thermal stability of the mutant protein, as compared to wild-type. Acc., solvent accessibility.
- Table S1. Structural impact of missense mutations detected in the current study and comparison with previously identified mutations (PDF, 39.1 KB) -
Mutations are classified as fold-stabilizing (S) or destabilizing (D), and the torsion angles as favorable (F) or unfavorable (U). (As assessed with CUPSAT). Unless otherwise indicated, values for G apply to thermal stability of the mutant protein, as compared to wild-type.
- Figure S1. Hypothetical structure of intrinsic Xase complex (JPG, 68.8 KB)
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The most likely conformation of the FVIIIa·FIXa (Xase) complex predicted by ZDOCK is shown. The cofactor is represented as a solid surface with domains color-coded as in Figures 1B and 5, and the cognate serine protease is shown as a transparent gray surface superimposed on a cartoon of the model. The approaching substrate, FX, is represented to the left as a transparent light pink surface superimposed on a cartoon of the model. All protein domains are labeled. Ca2+ and Mg2+ ions bound to the Gla domains of FIXa / FX are shown as wheat- and white/blue-colored spheres, respectively. Notice that multiple protein-protein contacts are formed between the concave “hemophilic surface” on FIXa (Brandstetter et al26) and cofactor domains A2, A3 and C1. The distances between serine protease and Gla domains of FIXa and FX are indicated as distances between C atoms of Leu6 and the catalytic Ser365(195) and between those of Phe4 and Ser379(195), respectively. Notice that they are similar to the ones between FVIIIa-a1 and the phospholipid membrane in the compact cofactor model (compare Figure 5). A detailed description of model generation and analysis will be presented elsewhere (Corral-Rodríguez et al, in preparation).
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