Authors
Maki Tsujita, Leticia Alves Da Silva, Kosuke Nakasuka, Junki Yamamoto, Robert C Ford, Thomas Stockner
Published in
Biochemistry and cell biology = Biochimie et biologie cellulaire. Aug 06, 2026. Epub Aug 06, 2026.
Abstract
High-density lipoprotein (HDL) functionality has emerged as a key determinant of residual cardiovascular risk despite advances in LDL-cholesterol lowering therapies. Small HDL particles, generated through ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux, are particularly effective in promoting cholesterol removal from macrophage foam cells and are associated with reduced atherosclerotic risk. Probucol, a lipid-lowering drug, inhibits ABCA1-dependent HDL biogenesis, whereas its major metabolite, 3,3',5,5'-tetra-tert-butyldiphenoquinone (DQ), preserves the generation of small HDL particles. However, the molecular basis for these distinct effects has remained unclear. To investigate the structural mechanisms underlying ABCA1-mediated lipid export, we performed molecular docking analyses using the human ABCA1 structure (PDB: 5XJY) and the GOLD in silico docking platform. Cholesterol and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) docking poses were successfully identified in DQ-bound ABCA1. In contrast, no ligand-binding poses were detected in probucol-bound ABCA1. These findings suggest that DQ preserves the lipid-recognition and transport properties of ABCA1, whereas probucol disrupts ligand accommodation within the transporter. This study provides the first atomic-level insight into the interactions among ABCA1, cholesterol, probucol, and DQ, offering a structural explanation for their distinct effects on HDL biogenesis and identifying a potential framework for developing novel HDL-targeted therapeutics.
PMID:
42561456
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.
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