6C1I

Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with T0070907

6C1I の概要

• エントリーDOI: 10.2210/pdb6c1i/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide, nonanoic acid, ... (4 entities in total)
• 機能のキーワード: nuclear receptors, tzds, drug design, therapeutic targets, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63558.61

構造登録者

Shang, J.,Fuhrmann, J.,Brust, R.,Kojetin, D.J. (登録日: 2018-01-04, 公開日: 2018-12-12, 最終更新日: 2024-10-23)

主引用文献

Brust, R.,Shang, J.,Fuhrmann, J.,Mosure, S.A.,Bass, J.,Cano, A.,Heidari, Z.,Chrisman, I.M.,Nemetchek, M.D.,Blayo, A.L.,Griffin, P.R.,Kamenecka, T.M.,Hughes, T.S.,Kojetin, D.J.
A structural mechanism for directing corepressor-selective inverse agonism of PPAR gamma.
Nat Commun, 9:4687-4687, 2018

PubMed 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.

PubMed: 30409975
DOI: 10.1038/s41467-018-07133-w

実験手法

X-RAY DIFFRACTION (2.26 Å)