6k5o

Development of Novel Lithocholic Acid Derivatives as Vitamin D Receptor AgonistsDevelopment of Novel Lithocholic Acid Derivatives as Vitamin D Receptor Agonists

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:
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.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vanhooke JL, Tadi BP, Benning MM, Plum LA, DeLuca HF. New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations. Arch Biochem Biophys. 2007 Apr 15;460(2):161-5. Epub 2006 Dec 12. PMID:17227670 doi:10.1016/j.abb.2006.11.029
↑ Masuno H, Kazui Y, Tanatani A, Fujii S, Kawachi E, Ikura T, Ito N, Yamamoto K, Kagechika H. Development of novel lithocholic acid derivatives as vitamin D receptor agonists. Bioorg Med Chem. 2019 Jul 3. pii: S0968-0896(19)30931-9. doi:, 10.1016/j.bmc.2019.07.003. PMID:31300316 doi:http://dx.doi.org/10.1016/j.bmc.2019.07.003

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OCA

[1] Vanhooke JL, Tadi BP, Benning MM, Plum LA, DeLuca HF. New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations. Arch Biochem Biophys. 2007 Apr 15;460(2):161-5. Epub 2006 Dec 12. PMID:17227670 doi:10.1016/j.abb.2006.11.029

[2] Masuno H, Kazui Y, Tanatani A, Fujii S, Kawachi E, Ikura T, Ito N, Yamamoto K, Kagechika H. Development of novel lithocholic acid derivatives as vitamin D receptor agonists. Bioorg Med Chem. 2019 Jul 3. pii: S0968-0896(19)30931-9. doi:, 10.1016/j.bmc.2019.07.003. PMID:31300316 doi:http://dx.doi.org/10.1016/j.bmc.2019.07.003

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