Download MendeleyCrystal structures of hereditary vitamin D-resistant rickets-associated vitamin D receptor mutants R270L and W282R bound to 1,25-dihydroxyvitamin D3 and synthetic ligands.
Nakabayashi, M., Tsukahara, Y., Iwasaki-Miyamoto, Y., Mihori-Shimazaki, M., Yamada, S., Inaba, S., Oda, M., Shimizu, M., Makishima, M., Tokiwa, H., Ikura, T., Ito, N.(2013) J Med Chem 56: 6745-6760
- PubMed: 23944708
- DOI: https://doi.org/10.1021/jm400537h
- Primary Citation of Related Structures:
3VT3, 3VT4, 3VT5, 3VT6, 3VT7, 3VT8, 3VT9 - PubMed Abstract:
The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, functions as a ligand-dependent transcription factor for various genes. Hereditary vitamin D-resistant rickets (HVDRR), an autosomal recessive disease, is caused by mutations in the VDR. In particular, the missense mutations R274L and W286R in the ligand-binding domain of the VDR can severely reduce or even eliminate natural hormone responsiveness. Here, we report a crystal structure analysis of the R270L and W282R mutants of rat VDR (human R274L and W286R, respectively) in complex with the natural hormone and synthetic ligands. We also studied the folding properties of the mutant proteins by using circular dichroism spectra. Our study indicates that these mutations result in only local structural modifications. We discuss why these mutations disrupt the VDR function and provide clues to develop effective ligands for the treatment of HVDRR.
Organizational Affiliation:
Graduate School of Biomedical Science, ‡Institute of Biomaterials and Bioengineering, and §Medical Research Institute, Tokyo Medical and Dental University , Bunkyo-ku, Tokyo 113-8510, Japan.
