6ONJ

Crystal structure of PPARgamma ligand binding domain in complex with TRAP220 peptide and agonist rosiglitazone

6ONJ の概要

• エントリーDOI: 10.2210/pdb6onj/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, Mediator of RNA polymerase II transcription subunit 1, TRAP220 Coactivator Peptide, 2,4-THIAZOLIDIINEDIONE, 5-[[4-[2-(METHYL-2-PYRIDINYLAMINO)ETHOXY]PHENYL]METHYL]-(9CL), ... (4 entities in total)
• 機能のキーワード: nuclear receptors, tzds, drug design, therapeutic targets, transcription, transcription-agonist complex, transcription/agonist
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34004.46

構造登録者

Shang, J.,Kojetin, D.J. (登録日: 2019-04-22, 公開日: 2020-03-04, 最終更新日: 2023-10-11)

主引用文献

Shang, J.,Mosure, S.A.,Zheng, J.,Brust, R.,Bass, J.,Nichols, A.,Solt, L.A.,Griffin, P.R.,Kojetin, D.J.
A molecular switch regulating transcriptional repression and activation of PPAR gamma.
Nat Commun, 11:956-956, 2020

PubMed Abstract: Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations.

PubMed: 32075969
DOI: 10.1038/s41467-020-14750-x

実験手法

X-RAY DIFFRACTION (2.3 Å)