5IAW

Novel natural FXR modulator with a unique binding mode

5IAW の概要

• エントリーDOI: 10.2210/pdb5iaw/pdb
• 分子名称: Bile acid receptor, Peptide from Nuclear receptor coactivator 2, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-hydroxybenzoate, ... (4 entities in total)
• 機能のキーワード: nuclear protein receptor, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus . Isoform 1: Nucleus . Isoform 2: Nucleus . Isoform 3: Nucleus . Isoform 4: Nucleus : Q96RI1
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 56611.34

構造登録者

Lu, Y.,Li, Y. (登録日: 2016-02-22, 公開日: 2017-03-08, 最終更新日: 2024-03-20)

主引用文献

Zheng, W.,Lu, Y.,Lin, S.,Wang, R.,Qiu, L.,Zhu, Y.,Yao, B.,Guo, F.,Jin, S.,Jin, L.,Li, Y.
A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co-regulator Assembly
Chembiochem, 18:721-725, 2017

PubMed Abstract: The farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce a conformational change in FXR that modulates its binding to co-regulators, thus resulting in distinct FXR functional profiles. However, the mechanisms for selectively recruiting co-regulators by FXR remain elusive, partly because of the lack of FXR-selective modulators. We report the identification of two natural terpenoids, tschimgine and feroline, as novel FXR modulators. Remarkably, their crystal structures uncovered a secondary binding pocket important for ligand binding. Further, tschimgine or feroline induced dynamic conformational changes in the activation function 2 (AF-2) surface, thus leading to differential co-regulator recruiting profiles, modulated by both hydrophobic and selective hydrogen-bond interactions unique to specific co-regulators. Our findings thus provide a novel structure template for optimization for FXR-selective modulators of clinical value.

PubMed: 28186695
DOI: 10.1002/cbic.201700059

実験手法

X-RAY DIFFRACTION (2.58 Å)