Significance ATP8B1 is a P4 ATPase that maintains membrane asymmetry by transporting phospholipids across the cell membrane. Disturbance of lipid asymmetry will lead to the imbalance of the cell membrane and eventually, cell death. Thus, defects in ATP8B1 are usually associated with severe human diseases, such as intrahepatic cholestasis. The present structures of ATP8B1 complexed with its auxiliary noncatalytic partners CDC50A and CDC50B reveal an autoinhibited state of ATP8B1 that could be released upon substrate binding. Moreover, release of this autoinhibition could be facilitated by the bile acids, which are key factors that alter the membrane asymmetry of hepatocytes. This enabled us to figure out a feedback loop of bile acids and lipids across the cell membrane.

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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.