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

Author:

Shang Jinsai1ORCID,Brust Richard1ORCID,Mosure Sarah A123ORCID,Bass Jared1,Munoz-Tello Paola1ORCID,Lin Hua4,Hughes Travis S56ORCID,Tang Miru7,Ge Qingfeng7,Kamenekca Theodore M4,Kojetin Douglas J14ORCID

Affiliation:

1. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States

2. Summer Undergraduate Research Fellows (SURF) program, The Scripps Research Institute, Jupiter, United States

3. Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, United States

4. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

5. Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, United States

6. Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, United States

7. Department of Chemistry and Biochemistry, Southern Illinois University, Carbondale, United States

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.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

American Heart Association

National Science Foundation

The Scripps Research Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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