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Structure–function relationships of vitamin D including ligand recognition by the vitamin D receptor
Author(s) -
Yamada Sachiko,
Shimizu Masato,
Yamamoto Keiko
Publication year - 2003
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.10023
Subject(s) - calcitriol receptor , ligand (biochemistry) , vitamin d and neurology , chemistry , stereochemistry , vitamin , side chain , receptor , vitamin d binding protein , docking (animal) , crystal structure , function (biology) , biochemistry , crystallography , biology , endocrinology , medicine , microbiology and biotechnology , nursing , organic chemistry , polymer
First, the general structure and function of nuclear receptors (NRs) are described briefly to help our understanding of the mechanism of action of vitamin D mediated by the vitamin D receptor (VDR), a member of the NRs. Then we discuss the structure–function relationship (SFR) of vitamin D on the basis of ligand structures and the interaction of the ligand with the VDR. The SFR of vitamin D side chain analogs is discussed extensively in terms of our active space group concept, which was derived from conformational analyses of the side chains of vitamin D analogs and from studies with conformationally restricted 22‐methyl‐1,25‐(OH) 2 D 3 isomers. The mobile area of the side chain of vitamin D can be grouped into five regions (E, G, EA, EG, and F), and the SFR has been analyzed in terms of these spatial regions. The SFR of ligand/VDR interaction is discussed on the basis of the crystal structure of VDR‐LBD(Δ165–215), docking of various vitamin D ligands into the ligand binding pocket (LBP) of the VDR, and functional analysis of amino acids lining the LBP. Finally, we discuss total SFR, combining the results of the two approaches, and future aspects of structure‐based design of vitamin D analogs. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 1, 89–115, 2003; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10023