4OIV

Structural basis for small molecule NDB as a selective antagonist of FXR

4OIV の概要

• エントリーDOI: 10.2210/pdb4oiv/pdb
• 分子名称: Bile acid receptor, N-benzyl-N-(3-tert-butyl-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino)benzamide (3 entities in total)
• 機能のキーワード: bile acid sensor, nuclear, nuclear protein receptor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : Q96RI1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53967.60

構造登録者

Xu, X.,Chen, L.,Hu, L.,Shen, X. (登録日: 2014-01-20, 公開日: 2015-03-25, 最終更新日: 2023-11-08)

主引用文献

Xu, X.,Xu, X.,Liu, P.,Zhu, Z.Y.,Chen, J.,Fu, H.A.,Chen, L.L.,Hu, L.H.,Shen, X.
Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXR alpha ) in Stabilizing the Homodimerization of the Receptor.
J.Biol.Chem., 290:19888-19899, 2015

PubMed Abstract: Farnesoid X receptor α (FXRα) as a bile acid sensor plays potent roles in multiple metabolic processes, and its antagonist has recently revealed special interests in the treatment of metabolic disorders, although the underlying mechanisms still remain unclear. Here, we identified that the small molecule N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide (NDB) functioned as a selective antagonist of human FXRα (hFXRα), and the crystal structure of hFXRα ligand binding domain (hFXRα-LBD) in complex with NDB was analyzed. It was unexpectedly discovered that NDB induced rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) by forming a homodimer of hFXRα-LBD, totally different from the active conformation in monomer state, and the binding details were further supported by the mutation analysis. Moreover, functional studies demonstrated that NDB effectively antagonized the GW4064-stimulated FXR/RXR interaction and FXRα target gene expression in primary mouse hepatocytes, including the small heterodimer partner (SHP) and bile-salt export pump (BSEP); meanwhile, administration of NDB to db/db mice efficiently decreased the gene expressions of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimer partner, and BSEP. It is expected that our first analyzed crystal structure of hFXRα-LBD·NDB will help expound the antagonistic mechanism of the receptor, and NDB may find its potential as a lead compound in anti-diabetes research.

PubMed: 26100621
DOI: 10.1074/jbc.M114.630475

実験手法

X-RAY DIFFRACTION (1.7 Å)