2Q5S

Crystal Structure of PPARgamma bound to partial agonist nTZDpa

2Q5S の概要

• エントリーDOI: 10.2210/pdb2q5s/pdb
• 関連するPDBエントリー: 2Q59 2Q5P 2Q61 2Q6R 2Q6S
• 分子名称: Peroxisome Proliferator-Activated Receptor gamma, 5-CHLORO-1-(4-CHLOROBENZYL)-3-(PHENYLTHIO)-1H-INDOLE-2-CARBOXYLIC ACID (3 entities in total)
• 機能のキーワード: protein-ligand complex, ligand binding protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P37231
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63447.29

構造登録者

Bruning, J.B.,Nettles, K.W. (登録日: 2007-06-01, 公開日: 2007-10-23, 最終更新日: 2023-08-30)

主引用文献

Bruning, J.B.,Chalmers, M.J.,Prasad, S.,Busby, S.A.,Kamenecka, T.M.,He, Y.,Nettles, K.W.,Griffin, P.R.
Partial Agonists Activate PPARgamma Using a Helix 12 Independent Mechanism
Structure, 15:1258-1271, 2007

PubMed Abstract: Binding to helix 12 of the ligand-binding domain of PPARgamma is required for full agonist activity. Previously, the degree of stabilization of the activation function 2 (AF-2) surface was thought to correlate with the degree of agonism and transactivation. To examine this mechanism, we probed structural dynamics of PPARgamma with agonists that induced graded transcriptional responses. Here we present crystal structures and amide H/D exchange (HDX) kinetics for six of these complexes. Amide HDX revealed each ligand induced unique changes to the dynamics of the ligand-binding domain (LBD). Full agonists stabilized helix 12, whereas intermediate and partial agonists did not at all, and rather differentially stabilized other regions of the binding pocket. The gradient of PPARgamma transactivation cannot be accounted for solely through changes to the dynamics of AF-2. Thus, our understanding of allosteric signaling must be extended beyond the idea of a dynamic helix 12 acting as a molecular switch.

PubMed: 17937915
DOI: 10.1016/j.str.2007.07.014

実験手法

X-RAY DIFFRACTION (2.05 Å)