Structure of Factor VII Gla domain bound to EPCR

The precise molecular determinants that underlie the binding of activated factor VII (FVIIa) to the endothelial cell protein C receptor (EPCR) have long remained unresolved. We report here the crystal structure of factor VII Gla domain bound to human EPCR, revealing a binding geometry in essence indistinguishable from that of the PC-EPCR interface and confirming absolute structural competition for EPCR binding. Relative to previous FVII structures, we observe receptor-dependent repositioning of the Gla {omega} loop coupled to a selective arrangement in which metal ion at position four adopts a Ca2+-compatible and EPCR-restricted coordination state. These findings resolve a long-standing gap and inform the structural basis for the binding of EPCR to FVIIa, a current therapeutic intervention in hemophilia.