Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ
- The Scripps Research Institute, United States
- University of Montana, United States
- Southern Illinois University, 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.
Data availability
Crystal structures and diffraction data have been deposited in the PDB under accession codes 5UGM, 6AVI, 6AUG, 6MCZ, 6MD0, 6MD1, 6MD2, and 6MD4.
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PPARgamma LBD complexed with rosiglitazoneBiological Magnetic Resonance Bank, 17975.
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Human PPAR gamma in complex with nonanoic acidsProtein Data Bank, 4EM9.
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Crystal Structure of PPARg in complex with T2384Protein Data Bank, 3K8S.
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Human PPAR gamma ligand binding domain in complex with MCC555Protein Data Bank, 3B0Q.
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.
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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Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ
eLife 7:e43320.
https://doi.org/10.7554/eLife.43320
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