Role of residues 143 and 278 of the human nuclear Vitamin D receptor in the full-length and Delta165-215 deletion mutant

The Journal of Steroid Biochemistry and Molecular Biology
Alejandra AcevedoElaine D Collins

Abstract

Most of the actions of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] are mediated by binding to the Vitamin D nuclear receptor (VDR). The crystal structure of a deletion mutant (Delta165-215) of the VDR ligand-binding domain (LBD) bound to 1,25(OH)(2)D(3) indicates that amino acid residues tyrosine-143 and serine-278 form hydrogen bonding interactions with the 3-hydroxyl group of 1,25(OH)(2)D(3). Studies of VDR and three mutants (Y143F, S278A, and Y143F/S278A) did not indicate any differences in the binding affinity between the variant receptors and the wild-type receptor. This might indicate that the 3-hydroxyl group binds differently to the full-length VDR than the to deletion mutant. To further investigate, four deletion VDR mutants were constructed: VDR(Delta165-215), VDR(Delta165-215) (Y143F), VDR(Delta165-215) (S278A), VDR(Delta165-215) (Y143F/S278A). There were no significant differences in binding affinity between the wild-type receptor and the deletion mutants except for VDR(Delta165-215) (Y143F/S278A). In gene activation assays, VDR constructs with the single mutation Y143F and the double mutation Y143F/S278A, but not the single mutation S278A required higher doses of 1,25(OH)(2)D(3) for half-maximal response. This sug...Continue Reading

References

May 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·A R BakerB W O'Malley
Apr 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·J S SackH M Einspahr
Jun 27, 2001·Bioorganic & Medicinal Chemistry·M ChoiS Yamada

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Citations

Jan 13, 2006·Theoretical Biology & Medical Modelling·Trevor G MarshallFrances E Marshall
Jan 30, 2007·The Journal of Steroid Biochemistry and Molecular Biology·Madhuri D ReddyElaine D Collins
Nov 26, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lin-Yan WanJiang-Feng Wu
May 14, 2008·Clinica Chimica Acta; International Journal of Clinical Chemistry·Indra Ramasamy

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