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Structural insights into human ABCC4-mediated transport of platelet agonist and antagonist.

Yu ChenLiang WangWen-Tao HouZhihui ZhaKang XuCong-Zhao ZhouQiong LiYuxing Chen
Published in: Nature cardiovascular research (2023)
Human platelets contribute to hemostasis and thrombosis, the imbalance of which can cause cardiovascular diseases. The activation and accumulation of platelets can be induced by agonists or inhibited by antagonists. Thus, the human ABC transporter ABCC4, which pumps out platelet agonists and antagonists, might become a promising target for preventing cardiovascular diseases. Here we define five structures of human ABCC4: the apo and three complexed forms in the inward-facing conformation, in addition to an outward-facing occluded conformation upon ATP binding. Combined with biochemical assays, we structurally prove that U46619, a synthetic analog of the unstable agonist TXA 2 , and the antagonist aspirin are substrates of ABCC4. In addition, we found that the platelet antagonist dipyridamole is a strong competitive inhibitor against ABCC4. These complex structures also enable us to identify a transmembrane pocket in ABCC4 that provides a defined space for the rational design of specific platelet antagonists.
Keyphrases
  • endothelial cells
  • cardiovascular disease
  • induced pluripotent stem cells
  • high resolution
  • pulmonary embolism
  • cardiovascular events
  • cardiovascular risk factors
  • mass spectrometry