Structural highlights
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
Both 25 R- and 25 S-25-adamantyl-23-yne-26,27-dinor-1alpha,25-dihydroxyvitamin D3 (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki-Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25 S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1alpha,25-dihydroxyvitamin D3, 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), bone cells (MG63, osteocalcin 64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural analysis of 4b in complex with rat VDR-ligand binding domain (LBD) showed the highest Calpha positional shift from the 1/VDR-LBD complex at helix 11. Helix 11 of the 4b and 1 VDR-LBD complexes also showed significant differences in surface properties. These results suggest that 4b should be examined further as another candidate for a mild preventive osteoporosis agent.
25 S-Adamantyl-23-yne-26,27-dinor-1alpha,25-dihydroxyvitamin D3: Synthesis, Tissue Selective Biological Activities, and X-ray Crystal Structural Analysis of Its Vitamin D Receptor Complex.,Otero R, Ishizawa M, Numoto N, Ikura T, Ito N, Tokiwa H, Mourino A, Makishima M, Yamada S J Med Chem. 2018 Jul 23. doi: 10.1021/acs.jmedchem.8b00427. PMID:29989817[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Otero R, Ishizawa M, Numoto N, Ikura T, Ito N, Tokiwa H, Mourino A, Makishima M, Yamada S. 25 S-Adamantyl-23-yne-26,27-dinor-1alpha,25-dihydroxyvitamin D3: Synthesis, Tissue Selective Biological Activities, and X-ray Crystal Structural Analysis of Its Vitamin D Receptor Complex. J Med Chem. 2018 Jul 23. doi: 10.1021/acs.jmedchem.8b00427. PMID:29989817 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00427
