Butyl pocket formation in the vitamin D receptor strongly affects the agonistic or antagonistic behavior of ligands

Nobuko Yoshimoto, Yuta Sakamaki, Minoru Haeta, Akira Kato, Yuka Inaba, Toshimasa Itoh, Makoto Nakabayashi, Nobutoshi Ito, Keiko Yamamoto

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Previously, we reported that 22S-butyl-25,26,27-trinor-1α24- dihydroxyvitamin D 32 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a-c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands.

Original languageEnglish
Pages (from-to)4373-4381
Number of pages9
JournalJournal of medicinal chemistry
Volume55
Issue number9
DOIs
Publication statusPublished - May 10 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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