Comparison of loop structures around FVIII C2 residue, Asp2267. The crystal structures of recombinant C2 domains from FV (Macedo-Ribeiro et al72 ) and FVIII (Pratt et al8 ) were superimposed, and residues around the mutated Asp2267 (FVIII) and the topologically equivalent Gln2132 (FV) are shown. The main chains of factors V and VIII are represented as orange and green ribbons, respectively. Only side chains of Gln2132/Asp2267 and surrounding residues are shown with all their nonhydrogen atoms; the side chains of FV are in orange and those of FVIII are color-coded as in Figure 3. Hydrogen bonds accepted from the Asp2267 carboxylate are indicated with dotted lines. Notice the complete equivalence of main-chain traces in the 2 cofactors, indicating that Asp2267 is dispensable for the observed loop conformation. Notice also that a large number of solvent-exposed side chains differ between the 2 cofactors, pointing to their involvement in specific protein-protein interactions. Inspection of the FVa/FVIIIa models suggests that these residues interact with substrates of the FVapi•FXa and FVIIIapi•FIXa complexes, prothrombin and FX, respectively.
