7CFO

Crystal structure of human RXRalpha ligand binding domain complexed with CBTF-EE.

7CFO の概要

• エントリーDOI: 10.2210/pdb7cfo/pdb
• 分子名称: Retinoic acid receptor RXR-alpha, 1-[3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl]-2-(trifluoromethyl)benzimidazole-5-carboxylic acid, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: retinoid x receptor alpha, antagonist, nuclear protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 110194.98

構造登録者

Watanabe, M.,Fujihara, M.,Motoyama, T.,Kawasaki, M.,Yamada, S.,Takamura, Y.,Ito, S.,Makishima, M.,Nakano, S.,Kakuta, H. (登録日: 2020-06-27, 公開日: 2021-01-06, 最終更新日: 2024-11-06)

主引用文献

Watanabe, M.,Fujihara, M.,Motoyama, T.,Kawasaki, M.,Yamada, S.,Takamura, Y.,Ito, S.,Makishima, M.,Nakano, S.,Kakuta, H.
Discovery of a "Gatekeeper" Antagonist that Blocks Entry Pathway to Retinoid X Receptors (RXRs) without Allosteric Ligand Inhibition in Permissive RXR Heterodimers.
J.Med.Chem., 64:430-439, 2021

PubMed Abstract: Retinoid X receptor (RXR) heterodimers such as PPAR/RXR, LXR/RXR, and FXR/RXR can be activated by RXR agonists alone and are therefore designated as permissive. Similarly, existing RXR antagonists show allosteric antagonism toward partner receptor agonists in these permissive RXR heterodimers. Here, we show 1-(3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-1-benzo[]imidazole-5-carboxylic acid (, CBTF-EE) as the first RXR antagonist that does not show allosteric inhibition in permissive RXR heterodimers. This compound was designed based on the hypothesis that RXR antagonists that do not induce conformational changes of RXR would not exhibit such allosteric inhibition. CD spectra and X-ray co-crystallography of the complex of and the RXR ligand binding domain (LBD) confirmed that does not change the conformation of hRXR-LBD. The X-ray structure analysis revealed that binds at the entrance of the ligand binding pocket (LBP), blocking access to the LBP and thus serving as a "gatekeeper".

PubMed: 33356247
DOI: 10.1021/acs.jmedchem.0c01354

実験手法

X-RAY DIFFRACTION (2.15 Å)