Structural insights into human ABCC4 mediated transport of platelet agonist and inhibitor

Abstract

The activation and accumulation of human platelets contributes to hemostasis and thrombosis, the imbalance of which would cause cardiovascular diseases, an increasing threat to the global health. Human ABC transporter ABCC4 that pumps out the platelet agonist and anti-platelet drug such as aspirin, might become a promising target for preventing cardiovascular diseases. Here we solve the structures of human ABCC4 in the apo and two complexed forms, all of which adopt a typical architecture of type-IV ABC transporters in an inward-facing conformation. Structure of ABCC4 complexed with U46619, an analog of the unstable TXA2, provides the first structural evidence that the platelet agonist TXA2is also exported via ABCC4. The dipyridamole-complexed structure reveals the inhibitory mechanism of dipyridamole against ABCC4. Structural comparisons enabled us to identify a transmembrane pocket in ABCC4 that provides a defined space for the rational design of specific anti-platelet drugs.