7c7w
Vitamin D3 receptor/lithochoric acid derivative complex
Structural highlights
FunctionVDR_RAT Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Recruited to promoters via its interaction with the WINAC complex subunit BAZ1B/WSTF, which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.[1] Publication Abstract from PubMedLithocholic acid (2) 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 2. Among the synthesized compounds, 6 bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3alpha-position of 2 showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10â¯000 times more potent than lithocholic acid (2) and 3 times more potent than 1alpha,25-dihydroxyvitamin D(3) (1). Although the binding affinities of 6 and its epimer 7 were less than that of 1, their transactivation activities were greater than that of 1. X-ray structure analyses of VDR LBD bound to 6 or 7 showed that the binding positions of these compounds in the ligand-binding pocket are similar to that of 1. Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists.,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 J Med Chem. 2021 Jan 14;64(1):516-526. doi: 10.1021/acs.jmedchem.0c01420. Epub , 2020 Dec 28. PMID:33369416[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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