7C7W

Vitamin D3 receptor/lithochoric acid derivative complex

Summary for 7C7W

• Entry DOI: 10.2210/pdb7c7w/pdb
• Descriptor: Vitamin D3 receptor, Mediator of RNA polymerase II transcription subunit 1, (4R)-4-[(3S,5R,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3-(2-methyl-2-oxidanyl-propyl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid, ... (5 entities in total)
• Functional Keywords: vitamin d receptor, transcription
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 32644.64

Authors

Masuno, H.,Numoto, N.,Kagechika, H.,Ito, N. (deposition date: 2020-05-26, release date: 2021-01-20, Last modification date: 2023-11-29)

Primary citation

Sasaki, H.,Masuno, H.,Kawasaki, H.,Yoshihara, A.,Numoto, N.,Ito, N.,Ishida, H.,Yamamoto, K.,Hirata, N.,Kanda, Y.,Kawachi, E.,Kagechika, H.,Tanatani, A.
Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists.
J.Med.Chem., 64:516-526, 2021

PubMed Abstract: Lithocholic acid () was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR-ligand-binding domain (LBD) bound to . Among the synthesized compounds, bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid () and 3 times more potent than 1α,25-dihydroxyvitamin D (). Although the binding affinities of and its epimer were less than that of , their transactivation activities were greater than that of . X-ray structure analyses of VDR LBD bound to or showed that the binding positions of these compounds in the ligand-binding pocket are similar to that of .

PubMed: 33369416
DOI: 10.1021/acs.jmedchem.0c01420

Experimental method

X-RAY DIFFRACTION (1.9 Å)