6VZL

Crystal structure of human PPARgamma ligand binding domain in complex with GW1929

6VZL の概要

• エントリーDOI: 10.2210/pdb6vzl/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, (2~{S})-3-[4-[2-[methyl(pyridin-2-yl)amino]ethoxy]phenyl]-2-[[2-(phenylcarbonyl)phenyl]amino]propanoic acid (3 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: 63890.18

構造登録者

Shang, J.,Kojetin, D.J. (登録日: 2020-02-28, 公開日: 2021-03-03, 最終更新日: 2023-10-11)

主引用文献

Shang, J.,Kojetin, D.J.
Structural mechanism underlying ligand binding and activation of PPAR gamma.
Structure, 29:940-950.e4, 2021

PubMed Abstract: Ligands bind to an occluded orthosteric ligand-binding pocket within the nuclear receptor ligand-binding domain. Molecular simulations have revealed theoretical ligand entry/exit pathways to the orthosteric pocket; however, it remains unclear whether ligand binding proceeds through induced fit or conformational selection mechanisms. Here, using nuclear magnetic resonance spectroscopy, isothermal titration calorimetry, and surface plasmon resonance analysis, we provide evidence that structurally distinct agonists bind peroxisome proliferator-activated receptor γ (PPARγ) via a two-step induced fit mechanism involving an initial fast kinetic step followed by a slow conformational change. The agonist encounter complex binding pose is suggested in crystal structures where ligands bind to a surface pore suggested as a ligand entry site in molecular simulations. Our findings suggest an activation mechanism for PPARγ whereby agonist binding occurs through an initial encounter complex followed by a transition of the ligand into the final binding pose within the orthosteric pocket, inducing a transcriptionally active conformation.

PubMed: 33713599
DOI: 10.1016/j.str.2021.02.006

実験手法

X-RAY DIFFRACTION (2.07 Å)