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 journalArticlepeer-review

21 Citations (Scopus)


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
Issue number1-2
Publication statusPublished - Jul 2010


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

ASJC Scopus subject areas

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


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