6DGO

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

6DGO の概要

• エントリーDOI: 10.2210/pdb6dgo/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, (5S)-5-[(4-{[(2R)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-yl]methoxy}phenyl)methyl]-1,3-thiazolidine-2,4-dione (2 entities in total)
• 機能のキーワード: nuclear receptors, tzds, drug design, therapeutic targets, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 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: 63340.58

構造登録者

Shang, J.,Kojetin, D.J. (登録日: 2018-05-17, 公開日: 2019-05-22, 最終更新日: 2023-10-11)

主引用文献

Shang, J.,Brust, R.,Griffin, P.R.,Kamenecka, T.M.,Kojetin, D.J.
Quantitative structural assessment of graded receptor agonism.
Proc.Natl.Acad.Sci.USA, 116:22179-22188, 2019

PubMed Abstract: Ligand-receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is critical to fully validate theoretical models. We applied quantitative structure-function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). For all ligands, agonist functional efficacy is correlated to a shift in the conformational ensemble equilibrium from a ground state toward an active state, which is detected by NMR spectroscopy but not observed in crystal structures. For the structurally similar ligands, ligand potency and affinity are also correlated to efficacy and conformation, indicating ligand residence times among related analogs may influence receptor conformation and function. Our results derived from quantitative graded activity-conformation correlations provide experimental evidence and a platform with which to extend and test theoretical models of receptor pharmacology to more accurately describe and predict ligand-dependent receptor activity.

PubMed: 31611383
DOI: 10.1073/pnas.1909016116

実験手法

X-RAY DIFFRACTION (3.1 Å)