TY - JOUR TI - Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ AU - Shang, Jinsai AU - Brust, Richard AU - Mosure, Sarah A AU - Bass, Jared AU - Munoz-Tello, Paola AU - Lin, Hua AU - Hughes, Travis S AU - Tang, Miru AU - Ge, Qingfeng AU - Kamenekca, Theodore M AU - Kojetin, Douglas J A2 - Kuriyan, John VL - 7 PY - 2018 DA - 2018/12/21 SP - e43320 C1 - eLife 2018;7:e43320 DO - 10.7554/eLife.43320 UR - https://doi.org/10.7554/eLife.43320 AB - 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. KW - nuclear receptors KW - nuclear magnetic resonance KW - x-ray crystallography KW - ligand binding KW - transcription factors JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -