9KNF

Crystal structure of human ERRg LBD in complex with 4028691

これはPDB形式変換不可エントリーです。

9KNF の概要

• エントリーDOI: 10.2210/pdb9knf/pdb
• 分子名称: Estrogen-related receptor gamma, Nuclear receptor-interacting protein 1, 5-chloranyl-2~{H}-indazole, ... (4 entities in total)
• 機能のキーワード: esrrg, lbd, nuclear receptor, complex structure, transcription
• 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: 30232.52

構造登録者

Xu, T.,Wang, N.,Liu, J. (登録日: 2024-11-18, 公開日: 2025-04-16, 最終更新日: 2025-09-10)

主引用文献

Shuai, Y.Y.,Zhang, H.Y.,Chen, R.,Wang, B.L.,Ding, P.,Dong, Y.,Sun, M.Z.,Wu, X.S.,Xu, Y.,Zhang, Y.,Liu, J.S.,Wang, N.,Xu, T.T.
Identification of indoles as potential endogenous ligands of ERR gamma and their modulation on drug binding.
Acta Pharmacol.Sin., 46:2574-2582, 2025

PubMed Abstract: Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor in the ERR subfamily that plays a crucial role in regulating energy metabolism. To date, no endogenous ligand has been identified for ERRγ, posing a challenge for developing targeted therapeutics. Here, we identified that indole and skatole produced by the gut microbiota are potential endogenous ligands of ERRγ using biochemical, cellular, structural, and computational approaches. Indole and skatole increased ERRγ thermostability and directly bound to the ligand-binding domain (LBD) with a K of approximately 1-2 μM but had no significant effect or weak inhibitory activity on the transcriptional efficiency. However, RNA sequencing revealed that ERRγ could coregulate several lipid metabolism- and immune-related genes with indole, suggesting a role for ERRγ in the indole pathway. Interestingly, indole and skatole differentially attenuated the activities of ERRγ ligands: they both neutralized the agonistic activity of GSK4716, while indole reduced the antagonistic activity of 4-hydroxytamoxifen (4OHT) and GSK5182, and skatole affected the agonistic activity of endocrine disruptor bisphenol A (BPA). We further screened additional indole metabolites and analogs, resolved the complex structures of ERRγ-LBD with these compounds, and conducted molecular dynamics simulations to determine their binding site and elucidate their binding mechanisms. This study identified potential endogenous ligands of ERRγ, suggesting a novel link between the energy metabolism regulation and the indole pathway. Our findings highlight the need to consider endogenous ligands when designing and optimizing ERRγ-targeted drugs.

PubMed: 40200124
DOI: 10.1038/s41401-025-01550-6

実験手法

X-RAY DIFFRACTION (1.62 Å)