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.
authors: Institute for Chemical Research, Kyoto University, Uji, Kyoto, Japan.
authors: Lisa
authors: L
authors: Asano
authors: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors: Tsuyoshi
authors: T
authors: Waku
authors: Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo, Japan.
authors: Rumi
authors: R
authors: Abe
authors: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan.
authors: Naoyuki
authors: N
authors: Kuwabara
authors: Graduate School of Life and Environmental Sciences/Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors: Ichiaki
authors: I
authors: Ito
authors: Graduate School of Life and Environmental Sciences/Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors: Junn
authors: J
authors: Yanagisawa
authors: Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo, Japan.
authors: Kazuo
authors: K
authors: Nagasawa
authors: Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan. shimizu@mol.f.u-tokyo.ac.jp.
authors: Toshiyuki
authors: T
authors: Shimizu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007769:Lactams / Q000737:chemistry*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000378:metabolism
chemical_list: D007769:Lactams; D018167:Receptors, Calcitriol; D002117:Calcitriol
keywords: crystal structure; vitamin D lactam derivative; vitamin D receptor