7vqp
Vitamin D receptor complexed with a lithocholic acid derivative
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 PubMed1alpha,25-Dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3), 1] is an active form of vitamin D(3) and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1alpha,25(OH)(2)D(3), (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3. Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists.,Yoshihara A, Kawasaki H, Masuno H, Takada K, Numoto N, Ito N, Hirata N, Kanda Y, Ishizawa M, Makishima M, Kagechika H, Tanatani A Biomolecules. 2022 Jan 14;12(1):130. doi: 10.3390/biom12010130. PMID:35053278[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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