4JYI

Crystal structure of RARbeta LBD in complex with selective partial agonist BMS641 [3-chloro-4-[(E)-2-(5,5-dimethyl-8-phenyl-5,6-dihydronaphthalen-2-yl)ethenyl]benzoic acid]

4JYI の概要

• エントリーDOI: 10.2210/pdb4jyi/pdb
• 関連するPDBエントリー: 1XAP 4DM6 4DM8 4JYG 4JYH
• 分子名称: Retinoic acid receptor beta, Nuclear receptor coactivator 1, 3-chloro-4-[(E)-2-(5,5-dimethyl-8-phenyl-5,6-dihydronaphthalen-2-yl)ethenyl]benzoic acid, ... (5 entities in total)
• 機能のキーワード: ligand binding domain, nuclear hormone receptor, transcription-agonist complex, transcription/agonist
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Isoform Beta-1: Nucleus. Isoform Beta-2: Nucleus. Isoform Beta-4: Cytoplasm: P10826; Nucleus : Q15788
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 64596.71

構造登録者

Nadendla, E.K.,Teyssier, C.,Germain, P.,Delfosse, V.,Bourguet, W. (登録日: 2013-03-29, 公開日: 2014-03-19, 最終更新日: 2024-02-28)

主引用文献

Nadendla, E.,Teyssier, C.,Delfosse, V.,Vivat, V.,Krishnasamy, G.,Gronemeyer, H.,Bourguet, W.,Germain, P.
An Unexpected Mode Of Binding Defines BMS948 as A Full Retinoic Acid Receptor beta (RAR beta , NR1B2) Selective Agonist.
Plos One, 10:e0123195-e0123195, 2015

PubMed Abstract: Retinoic acid is an important regulator of cell differentiation which plays major roles in embryonic development and tissue remodeling. The biological action of retinoic acid is mediated by three nuclear receptors denoted RARα, β and γ. Multiple studies support that RARβ possesses functional characteristics of a tumor suppressor and indeed, its expression is frequently lost in neoplastic tissues. However, it has been recently reported that RARβ could also play a role in mammary gland tumorigenesis, thus demonstrating the important but yet incompletely understood function of this receptor in cancer development. As a consequence, there is a great need for RARβ-selective agonists and antagonists as tools to facilitate the pharmacological analysis of this protein in vitro and in vivo as well as for potential therapeutic interventions. Here we provide experimental evidences that the novel synthetic retinoid BMS948 is an RARβ-selective ligand exhibiting a full transcriptional agonistic activity and activating RARβ as efficiently as the reference agonist TTNPB. In addition, we solved the crystal structures of the RARβ ligand-binding domain in complex with BMS948 and two related compounds, BMS641 and BMS411. These structures provided a rationale to explain how a single retinoid can be at the same time an RARα antagonist and an RARβ full agonist, and revealed the structural basis of partial agonism. Finally, in addition to revealing that a flip by 180° of the amide linker, that usually confers RARα selectivity, accounts for the RARβ selectivity of BMS948, the structural analysis uncovers guidelines for the rational design of RARβ-selective antagonists.

PubMed: 25933005
DOI: 10.1371/journal.pone.0123195

実験手法

X-RAY DIFFRACTION (1.9 Å)