Crystal Structure of EMS16 in Complex with the Integrin α2-I Domain

Abstract

Snake venoms contain a number of heterodimeric C-type lectin-like proteins (CLPs) that interact specifically with components of the haemostatic system. EMS16 from the venom of Echis multisquamatus binds to the collagen receptor, integrin α2β1, also known as glycoprotein (GP) Ia/IIa, and specifically inhibits collagen binding. Here we report the crystal structure of EMS16 in complex with recombinant integrin α2-I domain that plays a central role in collagen binding. The structure of the complex at 1.9Å resolution reveals that the collagen-binding site of the α2-I domain is covered completely by the bound EMS16. This blockage by EMS16 appears to spatially inhibit collagen binding to the α2-I domain. The bound α2-I domain adopts a closed conformation, which is seen in the absence of ligand, suggesting that EMS16 stabilizes a closed conformation corresponding to the less active structure of the α2-I domain. EMS16 does not directly bind to the manganese ion and residues of the metal ion-dependent adhesion site (MIDAS) of the α2-I domain, suggesting that EMS16 may have the potential to bind specifically to the α2-I domain in a metal ion-independent fashion.