8FKD

Crystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and inverse agonist SR33068

8FKD の概要

• エントリーDOI: 10.2210/pdb8fkd/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, Nuclear receptor corepressor 1, 2-chloro-N-(6-cyanopyridin-3-yl)-5-nitrobenzamide, ... (5 entities in total)
• 機能のキーワード: nuclear receptors, tzds, drug design, therapeutic targets, transcription, transcription-agonist complex
• 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: 34504.28

構造登録者

MacTavish, B.S.,Kojetin, D.J. (登録日: 2022-12-21, 公開日: 2024-04-17, 最終更新日: 2025-04-30)

主引用文献

MacTavish, B.S.,Zhu, D.,Shang, J.,Shao, Q.,He, Y.,Yang, Z.J.,Kamenecka, T.M.,Kojetin, D.J.
Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.
Nat Commun, 16:2065-2065, 2025

PubMed Abstract: Nuclear receptors (NRs) are thought to dynamically alternate between transcriptionally active and repressive conformations, which are stabilized upon ligand binding. Most NR ligand series exhibit limited bias, primarily consisting of transcriptionally active agonists or neutral antagonists, but not repressive inverse agonists-a limitation that restricts understanding of the functional NR conformational ensemble. Here, we report a NR ligand series for peroxisome proliferator-activated receptor gamma (PPARγ) that spans a pharmacological spectrum from repression (inverse agonism) to activation (agonism) where subtle structural modifications switch compound activity. While crystal structures provide snapshots of the fully repressive state, NMR spectroscopy and conformation-activity relationship analysis reveals that compounds within the series shift the PPARγ conformational ensemble between transcriptionally active and repressive conformations that are natively populated in the apo/ligand-free ensemble. Our findings reveal a molecular framework for minimal chemical modifications that enhance PPARγ inverse agonism and elucidate their influence on the dynamic PPARγ conformational ensemble.

PubMed: 40021712
DOI: 10.1038/s41467-025-57325-4

実験手法

X-RAY DIFFRACTION (2.22 Å)