6A5W

FXR-LBD with HNC143 and SRC1

6A5W の概要

• エントリーDOI: 10.2210/pdb6a5w/pdb
• 分子名称: Bile acid receptor, Nuclear receptor coactivator 1, 2-[2-[[3-[2,6-bis(chloranyl)phenyl]-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-6-azaspiro[3.4]octan-6-yl]-1,3-benzothiazole-6-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: nuclear receptor, coactivator, agonist, complex, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 57657.64

構造登録者

Wang, N.,Liu, J. (登録日: 2018-06-25, 公開日: 2018-10-10, 最終更新日: 2023-11-22)

主引用文献

Wang, N.,Zou, Q.,Xu, J.,Zhang, J.,Liu, J.
Ligand binding and heterodimerization with retinoid X receptor alpha (RXR alpha ) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding
J. Biol. Chem., 293:18180-18191, 2018

PubMed Abstract: Nuclear receptor farnesoid X receptor (FXR) functions as the major bile acid sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. Because of its central role in metabolism, FXR represents an important drug target to manage metabolic and other diseases, such as primary biliary cirrhosis and nonalcoholic steatohepatitis. FXR and nuclear receptor retinoid X receptor α (RXRα) form a heterodimer that controls the expression of numerous downstream genes. To date, the structural basis and functional consequences of the FXR/RXR heterodimer interaction have remained unclear. Herein, we present the crystal structures of the heterodimeric complex formed between the ligand-binding domains of human FXR and RXRα. We show that both FXR and RXR bind to the transcriptional coregulator steroid receptor coactivator 1 with higher affinity when they are part of the heterodimer complex than when they are in their respective monomeric states. Furthermore, structural comparisons of the FXR/RXRα heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce conformational changes in the C terminus of helix 11 in FXR that affect the stability of the coactivator binding surface and the coactivator binding in FXR. In summary, our findings shed light on the allosteric signal transduction in the FXR/RXR heterodimer, which may be utilized for future drug development targeting FXR.

PubMed: 30275017
DOI: 10.1074/jbc.RA118.004652

実験手法

X-RAY DIFFRACTION (2.88 Å)