Interaction of fVa with fXa in prothrombinase. (A) Overall structure of fVa in surface representation, oriented as in Figures 1B and 2B, showing the residues involved in recognition of fXa (yellow) and prothrombin (cyan). The interaction with fXa involves mainly the A2 domain and few contacts in the A3 and C1 domains (Table 2). Residues in the 694 to 699 region (Table 2) are labeled as a group. The entire 672 to 691 segment (gray) moves >7 Å relative to the position in free fV³⁵ to close like a lid over the protease domain of fXa. Also shown are the sites of inactivation by activated protein C at R306 and R506 (red) and the site of thrombin activation of fV at R709 (purple). (B) Surface representation of the A2 domain of fVa oriented as in Figure 2A, with all other domains, fXa and prothrombin removed for clarity. The view reveals the individual residues of fVa important for fXa binding (yellow) and their position relative to the 672 to 691 segment (gray) and the epitopes for prothrombin binding (cyan). (C) Surface representation of the protease domain of fXa oriented as in Figure 2D and rotated 30° along the x-axis, with all other domains, fVa and prothrombin removed for clarity. Residues of the catalytic triad (green), with S379 replaced by Ala, are in the center. The view reveals the residues involved in fVa binding (yellow) as being located toward the C-terminal helix (K420, R434) and the 340 to 350 (c165-175) segment of the protease domain. Also shown are residues responsible for binding of prothrombin (cyan) around the active site entrance (Q240, K242, K33) and the Na⁺ site region (E372, R405, K408). Particularly important is the strong electrostatic coupling of R347 of fXa with E572 and E662 of fVa, as identified by biochemical studies.^59,60