Model for membrane-bound FVIII/FIXa complex.

To the left the FVIII model (domains as described in Figure 5) is anchored into a phospholipid membrane (denoted with white dashed line). The FVIII domains, helices, PL-binding loops, and chain termini are colored as in Figure 5, and β sheets are shown as flat ribbon arrows. APC cleavage sites Arg336 and Arg562 are marked with white spheres. FVIII regions implicated in FIXa binding (484-509, 511-530, 558-565, 707-712, and 1811-1818) are highlighted as magenta ribbons and labeled in the same color, as is residue Arg527. To the right, the crystal structure for porcine FIXa9 is placed with the Gla domain (modeled based on that of prothrombin fragment I) inserted into the membrane surface, and with the Gla, EGF1, EGF2, and serine protease (SP) domains marked. The β sheets are shown as flat ribbon arrows, N- and C-termini of the FIXa light and heavy chains are shown as solid spheres, and the covalent active site inhibitor FPR-CK9 as yellow sticks. Sequences implicated in FVIII binding (301-303 and 333-339) are highlighted as red ribbons and labeled in the same color. A red dashed circle also highlights a possible FVIII interaction site at the EGF1-EGF2 interface. The FVIII and FIXa structures were docked manually such that most of the interactive regions were placed in reasonable proximity, then separated along the horizontal axis by approximately 1.0 to 1.5 nm for clarity of display.