Regulation of the vitamin D receptor by vitamin D lactam derivatives

Lisa Asano; Tsuyoshi Waku; Rumi Abe; Naoyuki Kuwabara; Ichiaki Ito; Junn Yanagisawa; Kazuo Nagasawa; Toshiyuki Shimizu

doi:10.1002/1873-3468.12348

Regulation of the vitamin D receptor by vitamin D lactam derivatives

Lisa Asano, Tsuyoshi Waku, Rumi Abe, Naoyuki Kuwabara, Ichiaki Ito, Junn Yanagisawa, Kazuo Nagasawa, Toshiyuki Shimizu

Research output: Contribution to journal › Letter

4 Scopus citations

Abstract

The active metabolite of vitamin D₃, 1α,25-dihydroxyvitamin D₃, acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1α,25-dihydroxyvitamin D₃-26,23-lactams (DLAMs), which mimic vitamin D₃ metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation.

Original language	English (US)
Pages (from-to)	3270-3279
Number of pages	10
Journal	FEBS Letters
Volume	590
Issue number	18
DOIs	https://doi.org/10.1002/1873-3468.12348
State	Published - Sep 1 2016
Externally published	Yes

Keywords

crystal structure
vitamin D lactam derivative
vitamin D receptor

ASJC Scopus subject areas

Structural Biology
Biophysics
Biochemistry
Molecular Biology
Genetics
Cell Biology

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Asano, L., Waku, T., Abe, R., Kuwabara, N., Ito, I., Yanagisawa, J., Nagasawa, K., & Shimizu, T. (2016). Regulation of the vitamin D receptor by vitamin D lactam derivatives. FEBS Letters, 590(18), 3270-3279. https://doi.org/10.1002/1873-3468.12348

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title = "Regulation of the vitamin D receptor by vitamin D lactam derivatives",

abstract = "The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3, acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1α,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), which mimic vitamin D3 metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation.",

keywords = "crystal structure, vitamin D lactam derivative, vitamin D receptor",

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T1 - Regulation of the vitamin D receptor by vitamin D lactam derivatives

AU - Asano, Lisa

AU - Waku, Tsuyoshi

AU - Abe, Rumi

AU - Kuwabara, Naoyuki

AU - Ito, Ichiaki

AU - Yanagisawa, Junn

AU - Nagasawa, Kazuo

AU - Shimizu, Toshiyuki

PY - 2016/9/1

Y1 - 2016/9/1

N2 - The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3, acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1α,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), which mimic vitamin D3 metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation.

AB - The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3, acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1α,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), which mimic vitamin D3 metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation.

KW - crystal structure

KW - vitamin D lactam derivative

KW - vitamin D receptor

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