4OIV

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

Summary for 4OIV

• Entry DOI: 10.2210/pdb4oiv/pdb
• Descriptor: Bile acid receptor, N-benzyl-N-(3-tert-butyl-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino)benzamide (3 entities in total)
• Functional Keywords: bile acid sensor, nuclear, nuclear protein receptor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q96RI1
• Total number of polymer chains: 2
• Total formula weight: 53967.60

Authors

Xu, X.,Chen, L.,Hu, L.,Shen, X. (deposition date: 2014-01-20, release date: 2015-03-25, Last modification date: 2023-11-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.7 Å)