Structure of Factor VII Gla domain bound to EPCR

During the past few decades, numerous studies provided evidence for a productive interaction between activated factor VII (FVIIa) and the endothelial protein C receptor (EPCR). However, a structure that settles the docking orientation and binding signature was still lacking. 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. FVII Gla locks onto EPCR surface through the cooperative contribution of Ca2+ ions, residues of gamma carboxyglutamic acid and the hydrophobic omega-loop, essentially recapitulating PC docking, and confirming absolute structural competition for EPCR binding. These findings resolve a long-standing gap and inform the structural basis for the binding of a pharmacologically relevant coagulation factor to EPCR, illustrating the complete steric competition with PC. Such competition is dictated by a conserved Gla domain fold-driven mechanism of recognition with potential implications for pharmacological rFVIIa intervention in hemophilia.