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.
Article and author information
Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK101871)
- Douglas J Kojetin
American Heart Association (16- POST27780018)
- Richard Brust
National Science Foundation (1659594)
- Sarah A Mosure
The Scripps Research Institute
- Sarah A Mosure
National Institute of Diabetes and Digestive and Kidney Diseases (R00DK103116)
- Travis S Hughes
National Institute of Diabetes and Digestive and Kidney Diseases (F32DK108442)
- Richard Brust
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- John Kuriyan, University of California, Berkeley, United States
Publication history
- Received: November 3, 2018
- Accepted: December 18, 2018
- Accepted Manuscript published: December 21, 2018 (version 1)
- Version of Record published: January 3, 2019 (version 2)
Copyright
© 2018, Shang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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