5UGM

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

5UGM の概要

• エントリーDOI: 10.2210/pdb5ugm/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, (5R)-5-({4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1-benzothiophen-7-yl}methyl)-1,3-thiazolidine-2,4-dione, 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: 64168.75

構造登録者

Shang, J.,Kojetin, D.J. (登録日: 2017-01-09, 公開日: 2018-01-17, 最終更新日: 2024-03-06)

主引用文献

Shang, J.,Brust, R.,Mosure, S.A.,Bass, J.,Munoz-Tello, P.,Lin, H.,Hughes, T.S.,Tang, M.,Ge, Q.,Kamekencka, T.M.,Kojetin, D.J.
Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPAR gamma.
Elife, 7:-, 2018

PubMed Abstract: Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω)-loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative biochemical functional and cellular assays reveal that synthetic ligand and fatty acid cobinding can form a 'ligand link' to the Ω-loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

PubMed: 30575522
DOI: 10.7554/eLife.43320

実験手法

X-RAY DIFFRACTION (2.1 Å)