Vitamin D receptor: Ligand recognition and allosteric network

Keiko Yamamoto, Daijiro Abe, Nobuko Yoshimoto, Mihwa Choi, Kenji Yamagishi, Hiroaki Tokiwa, Masato Shimizu, Makoto Makishima, Sachiko Yamada

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

To investigate the allosteric effects of ligands in the function of nuclear receptors, we performed exhaustive alanine scanning mutational analysis (ASMA) of the residues lining the ligand-binding pocket (LBP) of the human vitamin D receptor. The effects of ligands were examined in this system (termed two-dimensional (2D) ASMA) using 10 structurally and biologically characteristic ligands that included agonists, partial agonists, and a full antagonist. The results clearly revealed the role and importance of all the amino acid residues lining the LBP and the relationships between ligand binding and transcriptional potency. 2D ASMA indicated ligand-specific ligand-protein interactions, which have key importance in determining the transactivation potency of the ligand. Taking the results as a whole, we suggest a ligand-mediated allosteric network through which information from ligands is transmitted to the interfaces with protein cofactors and which was shown to be linked to part of the network found by statistical coupling analysis.

Original languageEnglish (US)
Pages (from-to)1313-1324
Number of pages12
JournalJournal of Medicinal Chemistry
Volume49
Issue number4
DOIs
StatePublished - Feb 23 2006
Externally publishedYes

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Calcitriol Receptors
Ligands
Alanine
Cytoplasmic and Nuclear Receptors
Transcriptional Activation
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Yamamoto, K., Abe, D., Yoshimoto, N., Choi, M., Yamagishi, K., Tokiwa, H., ... Yamada, S. (2006). Vitamin D receptor: Ligand recognition and allosteric network. Journal of Medicinal Chemistry, 49(4), 1313-1324. https://doi.org/10.1021/jm050795q

Vitamin D receptor : Ligand recognition and allosteric network. / Yamamoto, Keiko; Abe, Daijiro; Yoshimoto, Nobuko; Choi, Mihwa; Yamagishi, Kenji; Tokiwa, Hiroaki; Shimizu, Masato; Makishima, Makoto; Yamada, Sachiko.

In: Journal of Medicinal Chemistry, Vol. 49, No. 4, 23.02.2006, p. 1313-1324.

Research output: Contribution to journalArticle

Yamamoto, K, Abe, D, Yoshimoto, N, Choi, M, Yamagishi, K, Tokiwa, H, Shimizu, M, Makishima, M & Yamada, S 2006, 'Vitamin D receptor: Ligand recognition and allosteric network', Journal of Medicinal Chemistry, vol. 49, no. 4, pp. 1313-1324. https://doi.org/10.1021/jm050795q
Yamamoto K, Abe D, Yoshimoto N, Choi M, Yamagishi K, Tokiwa H et al. Vitamin D receptor: Ligand recognition and allosteric network. Journal of Medicinal Chemistry. 2006 Feb 23;49(4):1313-1324. https://doi.org/10.1021/jm050795q
Yamamoto, Keiko ; Abe, Daijiro ; Yoshimoto, Nobuko ; Choi, Mihwa ; Yamagishi, Kenji ; Tokiwa, Hiroaki ; Shimizu, Masato ; Makishima, Makoto ; Yamada, Sachiko. / Vitamin D receptor : Ligand recognition and allosteric network. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 4. pp. 1313-1324.
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