Structural insights into human ABCC4-mediated transport of platelet agonist and antagonist.
Nat Cardiovasc Res
; 2(7): 693-701, 2023 Jul.
Article
in En
| MEDLINE
| ID: mdl-39195918
ABSTRACT
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 TXA2, 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Blood Platelets
/
Platelet Aggregation Inhibitors
/
Multidrug Resistance-Associated Proteins
Limits:
Humans
Language:
En
Journal:
Nat Cardiovasc Res
Year:
2023
Document type:
Article
Affiliation country:
China
Country of publication:
United kingdom