6k5o

Development of Novel Lithocholic Acid Derivatives as Vitamin D Receptor Agonists

spinqualitylabelsall models 6k5o, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6k5o is a 2 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: D0O Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function VDR_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. Publication Abstract from PubMed Lithocholic acid (2) was identified as the second endogenous ligand of vitamin D receptor (VDR), though its binding affinity to VDR and its vitamin D activity are very weak compared to those of the active metabolite of vitamin D3, 1alpha,25-dihydroxyvitamin D3 (1). 3-Acylated lithocholic acids were reported to be slightly more potent than lithocholic acid (2) as VDR agonists. Here, aiming to develop more potent lithocholic acid derivatives, we synthesized several derivatives bearing a 3-sulfonate/carbonate or 3-amino/amide substituent, and examined their differentiation-inducing activity toward human promyelocytic leukemia HL-60 cells. Introduction of a nitrogen atom at the 3-position of lithocholic acid (2) decreased the activity, but compound 6 bearing a 3-methylsulfonate group showed more potent activity than lithocholic acid (2) or its acylated derivatives. The binding of 6 to VDR was confirmed by competitive binding assay and X-ray crystallographic analysis of the complex of VDR ligand-binding domain (LBD) with 6. Development of novel lithocholic acid derivatives as vitamin D receptor agonists.,Masuno H, Kazui Y, Tanatani A, Fujii S, Kawachi E, Ikura T, Ito N, Yamamoto K, Kagechika H Bioorg Med Chem. 2019 Jul 3. pii: S0968-0896(19)30931-9. doi:, 10.1016/j.bmc.2019.07.003. PMID:31300316 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Vitamin D receptor 3D structures

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