Defining a conformational ensemble that directs activation of PPAR gamma

作者：Chrisman Ian M; Nemetchek Michelle D; de Vera Ian Mitchelle S; Shang Jinsai; Heidari Zahra; Long Yanan; Reyes Caballero Hermes; Galindo Murillo Rodrigo; Cheatham Thomas E III; Blayo Anne Laure; Shin Youseung; Fuhrmann Jakob; Griffin Patrick R; Kamenecka Theodore M; Kojetin Douglas J; Hughes Travis S^*

来源：Nature Communications, 2018, 9(1): 1794.

DOI：10.1038/s41467-018-04176-x

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.

• 出版日期2018-5-4