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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.

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
J Med Chem 56 6745-60 (2013)
Related entries: 3vt4, 3vt5, 3vt6, 3vt7, 3vt8, 3vt9

Cited: 12 times
EuropePMC logo PMID: 23944708

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.

Articles - 3vt3 mentioned but not cited (3)

  1. Side-Chain Conformational Preferences Govern Protein-Protein Interactions. Watkins AM, Bonneau R, Arora PS. J Am Chem Soc 138 10386-10389 (2016)
  2. A multidisciplinary approach disclosing unexplored Aflatoxin B1 roles in severe impairment of vitamin D mechanisms of action. Persico M, Sessa R, Cesaro E, Dini I, Costanzo P, Ritieni A, Fattorusso C, Grosso M. Cell Biol Toxicol 39 1275-1295 (2023)
  3. Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats. Nishikawa M, Murose N, Mano H, Yasuda K, Isogai Y, Kittaka A, Takano M, Ikushiro S, Sakaki T. Sci Rep 12 12517 (2022)


Reviews citing this publication (6)

  1. Vitamin D and Its Synthetic Analogs. Maestro MA, Molnár F, Carlberg C. J Med Chem 62 6854-6875 (2019)
  2. Structural considerations of vitamin D signaling. Molnár F. Front Physiol 5 191 (2014)
  3. Structure-activity relationship of nonsecosteroidal vitamin D receptor modulators. Yamada S, Makishima M. Trends Pharmacol Sci 35 324-337 (2014)
  4. Structural aspects of Vitamin D endocrinology. Rochel N, Molnár F. Mol Cell Endocrinol 453 22-35 (2017)
  5. Genetic disorders of nuclear receptors. Achermann JC, Schwabe J, Fairall L, Chatterjee K. J Clin Invest 127 1181-1192 (2017)
  6. Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery. Yasuda K, Nishikawa M, Mano H, Takano M, Kittaka A, Ikushiro S, Sakaki T. Int J Mol Sci 22 11839 (2021)

Articles citing this publication (3)



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