期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04176-x
关键词
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资金
- National Institutes of Health (NIH) [K99DK103116, R00DK103116, P20GM103546, DK101871, DK105825]
- National Science Foundation (NSF) [1359369]
- Direct For Biological Sciences
- Div Of Biological Infrastructure [1359369] Funding Source: National Science Foundation
The nuclear receptor ligand-binding domain (LBD) is a highly dynamic entity. Crystal structures have defined multiple low-energy LBD structural conformations of the activation function-2 (AF-2) co-regulator-binding surface, yet it remains unclear how ligand binding influences the number and population of conformations within the AF-2 structural ensemble. Here, we present a nuclear receptor co-regulator-binding surface structural ensemble in solution, viewed through the lens of fluorine-19 (F-19) nuclear magnetic resonance (NMR) and molecular simulations, and the response of this ensemble to ligands, co-regulator peptides and heterodimerization. We correlate the composition of this ensemble with function in peroxisome proliferator-activated receptor-gamma (PPAR gamma) utilizing ligands of diverse efficacy in co-regulator recruitment. While the co-regulator surface of apo PPAR gamma and partial-agonist-bound PPAR gamma is characterized by multiple thermodynamically accessible conformations, the full and inverse-agonist-bound PPAR gamma co-regulator surface is restricted to a few conformations which favor coactivator or corepressor binding, respectively.
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