Agkisacucetin β chain contacts GPIbα receptor at the β-switch loop in the leucine rich repeat domain.
Agkisacucetin α chain contacts GPIbα receptor C-terminal peptide after the leucine rich repeat domain.
Agkisacucetin is a snake C-type lectin-like protein (snaclec) isolated from the venom of Deinagkistrodon acutus (formerly Agkistrodon acutus), which is a novel anti-thrombotic drug candidate currently in phase 2 clinical trials. Agkisacucetin specifically recognizes the platelet receptor glycoprotein Ib α chain (GPIbα) to block GPIb and von Willebrand Factor (VWF) interaction. In this study, we solved the crystal structure of GPIbα N-terminal domain (residue 1-305) in complex with Agkisacucetin to understand their molecular recognition mechanism. Crystal structure showed that Agkisacucetin mainly contacts GPIbα at the C-terminal part of the conserved leucine rich repeat (LRR) domain (LRR-6 to LRR-8) and the previously described "β-switch" region through β chain. In addition, we found that Agkisacucetin α chain also contacts part of the GPIbα C-terminal peptide after the LRR domain through complementary charge interactions. This C-terminal peptide plays a key role in GPIbα and thrombin recognition. Therefore, our structure revealed that Agkisacucetin can sterically block the interaction of GPIb receptor with both VWF and thrombin proteins to inhibit platelet function. Our structural work provides key molecular insights into how an anti-thrombonic drug candidate recognizes GPIb receptor to modulate platelet function to inhibit thrombosis.