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bioRxiv · 10.1101/252817

Coincident binding of synthetic and natural ligands to the nuclear receptor PPARγ

Shang, J.·Brust, R.·Mosure, S. A.·Bass, J.·Munoz-Tello, P.·Lin, H.·Hughes, T. S.·Tang, M.·Ge, Q.·Kamekencka, T. M.·Kojetin, D. J.
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Abstract

Crystal structures of peroxisome proliferator-activated receptor gamma (PPAR{gamma}) 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{gamma} ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega ({Omega}) loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative functional assays reveal that synthetic ligand and fatty acid cobinding can form a \"ligand link\" to the {Omega} loop and synergistically affect the structure and function of PPAR{gamma}. 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.

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Shang, J., Brust, R., Mosure, S. A., Bass, J., Munoz-Tello, P., Lin, H., Hughes, T. S., Tang, M., Ge, Q., Kamekencka, T. M., Kojetin, D. J.. 2018-01-24. Coincident binding of synthetic and natural ligands to the nuclear receptor PPARγ. https://doi.org/10.1101/252817

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