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Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPAR?.


ABSTRACT: Crystal structures of peroxisome proliferator-activated receptor gamma (PPAR?) 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 PPAR? ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (?)-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 ?-loop and synergistically affect the structure and function of PPAR?. 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.

SUBMITTER: Shang J 

PROVIDER: S-EPMC6317912 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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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 sp  ...[more]

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