Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: Structural basis for vitamin D receptor antagonism and partial agonism

Makoto Nakabayashi, Sachiko Yamada, Nobuko Yoshimoto, Takashi Tanaka, Miharu Igarashi, Teikichi Ikura, Nobutoshi Ito, Makoto Makishima, Hiroaki Tokiwa, Hector F. DeLuca, Masato Shimizu

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Abstract

The X-ray crystal structures of the rat VDR ligand-binding domain complexed with 19-norvitamin D compounds that contain an adamantyl substituent at the side-chain terminus, 2a (ADTT), 2b (ADNY), and 2c (ADMI4) and a coactivator peptide derived from DRIP205 are reported. These compounds show a series of partial agonistic ( 10-75% efficacy)/antagonistic activities. All of these complexed receptors are crystallized in the canonical active conformation, regardless of their activity profiles. The bulky adamantyl side chain does not crowd helix 12 but protrudes into the gap formed by helix 11, loop 11-12, helix 3, and loop 6-7, thereby widening the ligand binding pocket. We suggest that these structural changes destabilize the active protein conformation and reduce its contribution to equilibrium among the active and inactive conformations. The coactivator peptide traps the minor active conformation, and the equilibrium shifts to the active conformation. As a result, these ligands show partial agonistic activities.

Original languageEnglish
Pages (from-to)5320-5329
Number of pages10
JournalJournal of medicinal chemistry
Volume51
Issue number17
DOIs
Publication statusPublished - Sep 11 2008

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Nakabayashi, M., Yamada, S., Yoshimoto, N., Tanaka, T., Igarashi, M., Ikura, T., Ito, N., Makishima, M., Tokiwa, H., DeLuca, H. F., & Shimizu, M. (2008). Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: Structural basis for vitamin D receptor antagonism and partial agonism. Journal of medicinal chemistry, 51(17), 5320-5329. https://doi.org/10.1021/jm8004477