Journal
ELIFE
Volume 7, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.43320
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [R01DK101871, 16-POST27780018, 1659594, R00DK103116, F32DK108442]
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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 biochemical functional and cellular 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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