22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity

Yuka Inaba, Makoto Nakabayashi, Toshimasa Itoh, Nobuko Yoshimoto, Teikichi Ikura, Nobutoshi Ito, Masato Shimizu, Keiko Yamamoto

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

We recently reported that 22S-butyl-1α,24R-dihydroxyvitamin D3 3 recovers the agonistic activity for vitamin D receptor (VDR), although its 25,26,27-trinor analog 2 is a potent VDR antagonist. To investigate the structural features involved in the recovery of agonism, we crystallized the ternary complex of VDR-ligand-binding domain, ligand 3 and coactivator peptide, and conducted X-ray crystallographic analysis of the complex. Compared with the complex with 2, the complex with 3 recovered the following structural features: a pincer-type hydrogen bond between the 24-hydroxyl group and VDR, the conformation of Leu305, the positioning of His301 and His393, the stability of the complex, and intimate hydrophobic interactions between the ligand and helix 12. In addition, we evaluated the potency of both compounds for recruiting RXR and coactivator. The results indicate that the complex with 3 generates a suitable surface for coactivator recruitment. These studies suggest that the action of 2 as an antagonist is caused by the generation of a surface not suitable for coactivator recruitment due to the lack of hydrophobic interactions with helix 12 as well as insufficient hydrogen bond formation between the 24-hydroxyl group and VDR. We concluded that the action of 3 as an agonist is based on the elimination of these structural defects in the complex with 2.

Original languageEnglish
Pages (from-to)146-150
Number of pages5
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume121
Issue number1-2
DOIs
Publication statusPublished - Jul 2010
Externally publishedYes

Fingerprint

Calcitriol Receptors
Recovery
Ligands
Hydrophobic and Hydrophilic Interactions
Hydroxyl Radical
Hydrogen
Hydrogen bonds
Conformations
X-Rays
dihydroxy-vitamin D3
X rays
Defects
Peptides

Keywords

  • Antagonist
  • Coactivator
  • Hydrophobic interaction
  • Nuclear receptor
  • X-ray crystallography

ASJC Scopus subject areas

  • Molecular Medicine
  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Cell Biology
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry
  • Medicine(all)

Cite this

22S-Butyl-1α,24R-dihydroxyvitamin D3 : Recovery of vitamin D receptor agonistic activity. / Inaba, Yuka; Nakabayashi, Makoto; Itoh, Toshimasa; Yoshimoto, Nobuko; Ikura, Teikichi; Ito, Nobutoshi; Shimizu, Masato; Yamamoto, Keiko.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 121, No. 1-2, 07.2010, p. 146-150.

Research output: Contribution to journalArticle

Inaba, Y, Nakabayashi, M, Itoh, T, Yoshimoto, N, Ikura, T, Ito, N, Shimizu, M & Yamamoto, K 2010, '22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity', Journal of Steroid Biochemistry and Molecular Biology, vol. 121, no. 1-2, pp. 146-150. https://doi.org/10.1016/j.jsbmb.2010.02.033
Inaba, Yuka ; Nakabayashi, Makoto ; Itoh, Toshimasa ; Yoshimoto, Nobuko ; Ikura, Teikichi ; Ito, Nobutoshi ; Shimizu, Masato ; Yamamoto, Keiko. / 22S-Butyl-1α,24R-dihydroxyvitamin D3 : Recovery of vitamin D receptor agonistic activity. In: Journal of Steroid Biochemistry and Molecular Biology. 2010 ; Vol. 121, No. 1-2. pp. 146-150.
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