3vt8 Citations

Crystal Structures of Hereditary Vitamin D-Resistant Rickets-Associated Vitamin D Receptor Mutants R270L and W282R Bound to 1,25-Dihydroxyvitamin D3 and Synthetic Ligands.

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.

Reviews citing this publication (2)

  1. Structure-activity relationship of nonsecosteroidal vitamin D receptor modulators. Yamada S, Makishima M. Trends Pharmacol. Sci. 35 324-337 (2014)
  2. Structural considerations of vitamin D signaling. Molnár F. Front Physiol 5 191 (2014)

Articles citing this publication (4)

  1. Combined sequence and sequence-structure based methods for analyzing FGF23, CYP24A1 and VDR genes. Nagamani S, Singh KhD, Muthusamy K. Meta Gene 9 26-36 (2016)
  2. Clinical and genetic findings in a Chinese family with VDR-associated hereditary vitamin D-resistant rickets. Pang Q, Qi X, Jiang Y, Wang O, Li M, Xing X, Dong J, Xia W. Bone Res 4 16018 (2016)
  3. Novel screening system for high-affinity ligand of heredity vitamin D-resistant rickets-associated vitamin D receptor mutant R274L using bioluminescent sensor. Mano H, Nishikawa M, Yasuda K, Ikushiro S, Saito N, Sawada D, Honzawa S, Takano M, Kittaka A, Sakaki T. J. Steroid Biochem. Mol. Biol. 167 61-66 (2017)
  4. Genetic disorders of nuclear receptors. Achermann JC, Schwabe J, Fairall L, Chatterjee K. J. Clin. Invest. 127 1181-1192 (2017)