Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ

Jinsai Shang, Richard Brust, Sarah A. Mosure, Jared Bass, Paola Munoz-Tello, Hua Lin, Travis S. Hughes, Miru Tang, Qingfeng Ge, Theodore M. Kamenekca, Douglas J. Kojetin

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

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. DOI: https://doi.org/10.7554/eLife.43320.001.

Original languageEnglish
Article numbere43320
JournaleLife
Volume7
DOIs
StatePublished - Dec 1 2018

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