7c7v

Vitamin D3 receptor/lithochoric acid derivative complexVitamin D3 receptor/lithochoric acid derivative complex

Structural highlights

7c7v 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 2Å
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 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.

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
↑ 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. 2021 Jan 14;64(1):516-526. PMID:33369416 doi:10.1021/acs.jmedchem.0c01420

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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] 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. 2021 Jan 14;64(1):516-526. PMID:33369416 doi:10.1021/acs.jmedchem.0c01420

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