A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor

Yuka Inaba, Nobuko Yoshimoto, Yuta Sakamaki, Makoto Nakabayashi, Teikichi Ikura, Hirokazu Tamamura, Nobutoshi Ito, Masato Shimizu, Keiko Yamamoto

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45 Citations (Scopus)

Abstract

To identify novel vitamin D receptor (VDR) ligands that induce a novel architecture within the ligand-binding pocket (LBP), we have investigated eight 22-butyl-1α,24-dihydroxyvitamin D3 derivatives (3-10), all having a butyl group as the branched alkyl side chain. We found that the 22S-butyl-20-epi-25,26,27- trinorvitamin D derivative 5 was a potent vDr agonist, whereas the corresponding compound 4 with the natural configuration at C(20) was a potent VDR antagonist. Analogues with the full vitamin D3 side chain were less potent agonist, and whether they were agonists or antagonists depended on the 24-configuration. X-ray crystal structures demonstrated that the VDR-LBD accommodating the potent agonist 5 has an architecture wherein the lower side and the helix 11 side of the LBP is simply expanded relative to the canonical active-VDR situation; in contrast, the potent antagonist 4 induces an extra cavity to accommodate the branched moiety. This is the first report of a VDR antagonist that generates a new cavity to alter the canonical pocket structure of the ligand occupied VDR.

Original languageEnglish
Pages (from-to)1438-1449
Number of pages12
JournalJournal of medicinal chemistry
Volume52
Issue number5
DOIs
Publication statusPublished - Mar 12 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Inaba, Y., Yoshimoto, N., Sakamaki, Y., Nakabayashi, M., Ikura, T., Tamamura, H., Ito, N., Shimizu, M., & Yamamoto, K. (2009). A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor. Journal of medicinal chemistry, 52(5), 1438-1449. https://doi.org/10.1021/jm8014348