A structural mechanism for directing inverse agonism of PPARγ

摘要: Small chemical modifications can have significant effects on ligand efficacy and receptor activity, but the underlying structural mechanisms be difficult to predict from static crystal structures alone. Here we show how a simple phenyl-to-pyridyl substitution between two common covalent orthosteric ligands targeting peroxisome proliferator-activated (PPAR) gamma (PPARγ) converts transcriptionally neutral antagonist (GW9662) into an inverse agonist (T0070907). X-ray crystallography, molecular dynamics simulations, mutagenesis coupled activity assays reveal water-mediated hydrogen bond network linking T0070907 pyridyl group Arg288 that is essential for agonism. NMR spectroscopy reveals PPARγ exchanges long-lived conformations when bound not GW9662, including conformation prepopulates corepressor-bound state, priming high affinity corepressor binding. Our findings demonstrate engagement of may provide new routes developing agonists.