Structural Determinants for Vitamin D Receptor Response to Endocrine and Xenobiotic Signals

Ryutaro Adachi, Andrew I. Shulman, Keiko Yamamoto, Iichiro Shimomura, Sachiko Yamada, David J. Mangelsdorf, Makoto Makishima

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

The vitamin D receptor (VDR), initially identified as a nuclear receptor for 1α,25-dihydroxyvitamin D3 [1α,25(OH) 2D3], regulates calcium metabolism, cellular proliferation and differentiation, immune responses, and other physiological processes. Recently, secondary bile acids such as lithocholic acid (LCA) were identified as endogenous VDR agonists. To identify structural determinants required for VDR activation by 1α,25(OH)2D3 and LCA, we generated VDR mutants predicted to modulate ligand response based on sequence homology to pregnane X receptor, another bile acid-responsive nuclear receptor. In both vitamin D response element activation and mammalian two-hybrid assays, we found that VDR-S278V is activated by 1α,25(OH) 2D3 but not by LCA, whereas VDR-S237M can respond to LCA but not to 1α,25(OH)2D3. Competitive ligand binding analysis reveals that LCA, but not 1α,25(OH)2D3, effectively binds to VDR-S237M and both 1α,25(OH)2D 3 and LCA bind to VDR-S278V. We propose a docking model for LCA binding to VDR that is supported by mutagenesis data. Comparative analysis of the VDR-LCA and VDR-1α,25(OH)2D3 structure-activity relationships should be useful in the development of bile acid-derived synthetic VDR ligands that selectively target VDR function in cancer and immune disorders without inducing adverse hypercalcemic effects.

Original languageEnglish (US)
Pages (from-to)43-52
Number of pages10
JournalMolecular Endocrinology
Volume18
Issue number1
DOIs
StatePublished - Jan 2004

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Calcitriol Receptors
Xenobiotics
Lithocholic Acid
Bile Acids and Salts
Cytoplasmic and Nuclear Receptors
Ligands
Vitamin D Response Element
Physiological Phenomena
Two-Hybrid System Techniques
Competitive Binding
Calcitriol
Immune System Diseases
Structure-Activity Relationship
Sequence Homology
Mutagenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Structural Determinants for Vitamin D Receptor Response to Endocrine and Xenobiotic Signals. / Adachi, Ryutaro; Shulman, Andrew I.; Yamamoto, Keiko; Shimomura, Iichiro; Yamada, Sachiko; Mangelsdorf, David J.; Makishima, Makoto.

In: Molecular Endocrinology, Vol. 18, No. 1, 01.2004, p. 43-52.

Research output: Contribution to journalArticle

Adachi, R, Shulman, AI, Yamamoto, K, Shimomura, I, Yamada, S, Mangelsdorf, DJ & Makishima, M 2004, 'Structural Determinants for Vitamin D Receptor Response to Endocrine and Xenobiotic Signals', Molecular Endocrinology, vol. 18, no. 1, pp. 43-52. https://doi.org/10.1210/me.2003-0244
Adachi, Ryutaro ; Shulman, Andrew I. ; Yamamoto, Keiko ; Shimomura, Iichiro ; Yamada, Sachiko ; Mangelsdorf, David J. ; Makishima, Makoto. / Structural Determinants for Vitamin D Receptor Response to Endocrine and Xenobiotic Signals. In: Molecular Endocrinology. 2004 ; Vol. 18, No. 1. pp. 43-52.
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