A Structural Mechanism for Directing Corepressor-selective Inverse Agonism of PPARγ

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Nov 10

PMID 30409975

Citations 24

Authors

Richard Brust

Jinsai Shang

Jakob Fuhrmann

Sarah A Mosure

Jared Bass

Andrew Cano

Zahra Heidari

Ian M Chrisman

Michelle D Nemetchek

Anne-Laure Blayo

Patrick R Griffin

Theodore M Kamenecka

Travis S Hughes

Douglas J Kojetin

Affiliations

Soon will be listed here.

Abstract

Small chemical modifications can have significant effects on ligand efficacy and receptor activity, but the underlying structural mechanisms can 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 receptor (PPAR) gamma converts a transcriptionally neutral antagonist (GW9662) into a repressive inverse agonist (T0070907) relative to basal cellular activity. X-ray crystallography, molecular dynamics simulations, and mutagenesis coupled to activity assays reveal a water-mediated hydrogen bond network linking the T0070907 pyridyl group to Arg288 that is essential for corepressor-selective inverse agonism. NMR spectroscopy reveals that PPARγ exchanges between two long-lived conformations when bound to T0070907 but not GW9662, including a conformation that prepopulates a corepressor-bound state, priming PPARγ for high affinity corepressor binding. Our findings demonstrate that ligand engagement of Arg288 may provide routes for developing corepressor-selective repressive PPARγ ligands.

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