6C5T

PPARg LBD bound to SR11023

6C5T の概要

• エントリーDOI: 10.2210/pdb6c5t/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, 2-{4-[(5-{[(1R)-1-(3-cyclopropylphenyl)ethyl]carbamoyl}-2,3-dimethyl-1H-indol-1-yl)methyl]phenyl}-2-methylpropanoic acid (3 entities in total)
• 機能のキーワード: peroxisome proliferator activated receptor gamma; pparg, nuclear receptor, inverse agonist, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32073.29

構造登録者

Bruning, J.B.,Frkic, R.L.,Griffin, P.R. (登録日: 2018-01-16, 公開日: 2018-08-01, 最終更新日: 2024-10-16)

主引用文献

Frkic, R.L.,Marshall, A.C.,Blayo, A.L.,Pukala, T.L.,Kamenecka, T.M.,Griffin, P.R.,Bruning, J.B.
PPAR gamma in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix.
iScience, 5:69-79, 2018

PubMed Abstract: Peroxisome proliferator activated receptor γ (PPARγ) is a nuclear receptor and target for antidiabetics that increase insulin sensitivity. Owing to the side effects of PPARγ full agonists, research has recently focused on non-activating ligands of PPARγ, which increase insulin sensitivity with decreased side effects. Here, we present the crystal structures of inverse agonist SR10171 and a chemically related antagonist SR11023 bound to the PPARγ ligand-binding domain, revealing an allosteric switch in the activation helix, helix 12 (H12), forming an antagonist conformation in the receptor. H12 interacts with the antagonists to become fixed in an alternative location. Native mass spectrometry indicates that this prevents contacts with coactivator peptides and allows binding of corepressor peptides. Antagonists of related nuclear receptors act to sterically prevent the active configuration of H12, whereas these antagonists of PPARγ alternatively trap H12 in an inactive configuration, which we have termed the tumble and trap mechanism.

PubMed: 30123887
DOI: 10.1016/j.isci.2018.06.012

実験手法

X-RAY DIFFRACTION (2.75 Å)