Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States; Summer Undergraduate Research Fellows (SURF) program, The Scripps Research Institute, Jupiter, United States; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, United States
Jared Bass
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, United States; Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, United States
Miru Tang
Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale, United States
Qingfeng Ge
Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale, United States
Theodore M Kamenekca
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω)-loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative biochemical functional and cellular assays reveal that synthetic ligand and fatty acid cobinding can form a ‘ligand link’ to the Ω-loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.
