Crystal structure of rhodocytin, a ligand for the platelet‐activating receptor CLEC‐2

AbstractBinding of the snake venom protein rhodocytin to CLEC‐2, a receptor on the surface of human platelets, initiates a signaling cascade leading to platelet activation and aggregation. We have previously solved the structure of CLEC‐2. The 2.4 Å resolution crystal structure of rhodocytin presented here demonstrates that it is the first snake venom or other C‐type lectin‐like protein to assemble as a non‐disulfide linked (αβ)2 tetramer. Rhodocytin is highly adapted for interaction with CLEC‐2 and displays a concave binding surface, which is highly complementary to the experimentally determined binding interface on CLEC‐2. Using computational dynamic methods, surface electrostatic charge and hydrophobicity analyses, and protein–protein docking predictions, we propose that the (αβ)2 rhodocytin tetramer induces clustering of CLEC‐2 receptors on the platelet surface, which will trigger major signaling events resulting in platelet activation and aggregation.