期刊
STRUCTURE
卷 20, 期 1, 页码 139-150出版社
CELL PRESS
DOI: 10.1016/j.str.2011.10.018
关键词
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资金
- James and Esther King Biomedical Research Program, Florida Department of Health [1KN-09]
- The Scripps,Research Institute
- U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences [R01-GM084041, R01-GM063855]
- National Center for Research Resources [RR19077, RR027755]
Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution nuclear magnetic resonance (NMR) studies that reveal peroxisome proliferator-activated receptor gamma (PPAR gamma) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPAR gamma modulators.
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