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Titolo:
Structure-function analysis of vitamin D and VDR model
Autore:
Yamada, S; Yamamoto, K; Masuno, H;
Indirizzi:
Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Chiyoda Ku, Tokyo 1010062, Japan Tokyo Med & Dent Univ Tokyo Japan 1010062 iyoda Ku, Tokyo 1010062, Japan
Titolo Testata:
CURRENT PHARMACEUTICAL DESIGN
fascicolo: 7, volume: 6, anno: 2000,
pagine: 733 - 748
SICI:
1381-6128(200005)6:7<733:SAOVDA>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
LIGAND-BINDING DOMAIN; DIFFERENTIATION-INDUCING ACTIVITY; THYROID-HORMONE RECEPTOR; SIDE-CHAIN CONFORMATION; BONE-MINERAL LOSS; NUCLEAR RECEPTOR; BIOLOGICAL-ACTIVITY; D ANALOGS; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; CRYSTAL-STRUCTURE;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
63
Recensione:
Indirizzi per estratti:
Indirizzo: Yamada, S Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Chiyoda Ku, 2-3-10Kanda Surugadai, Tokyo 1010062, Japan Tokyo Med & Dent Univ 2-3-10 Kanda Surugadai Tokyo Japan 1010062
Citazione:
S. Yamada et al., "Structure-function analysis of vitamin D and VDR model", CUR PHARM D, 6(7), 2000, pp. 733-748

Abstract

In the first section, the general three-dimensional structure of the ligand-binding domain (LBD) of nuclear receptors (NR) was briefly described on the basis of their x-ray crystal structures. Emphasis was placed on the three major conformations of NR-LBD and their role in the transactivation function. In the second part, the structure-function relationship of vitamin D was analyzed based on the ligand structure, in particular by using systematic conformational analysis as a tool. On the basis of the conformational analysis of the vitamin D side chain and studies using conformationally restricted synthetic vitamin D analogs, we suggested the active space region concept of vitamin D: The vitamin D side-chain region was grouped into five regions (A, G, EA, EG and F). Activity orders, in terms of the spatial region,found by these studies are as follows: Affinity for vitamin D receptor (VDR), EA>A>F>G>EG; Affinity for vitamin D binding protein (DBP), A>>C,EA,EG; Target gene transactivation, EA>F>A>EG greater than or equal to G: Cell differentiation, EA>F>A>EG greater than or equal to G; Bone calcium mobilization, EA>G greater than or equal to A>F greater than or equal to EG Intestinal calcium absorption, EA=A greater than or equal to G>>EG. In the third section, homology modeling of VDR-LBD and docking of the natural ligand, 1,25-(OH)(2)D-3, into the ligand binding cavity of the model are described. Amino acid residues forming hydrogen bonds with the biologically important 1 alpha- and 25-OH groups were identified: 1 alpha-OH forms a pincer-type hydrogen bond with R273 and S237 and 25-OH with H397. This VDR-LBD/1,25-(OH)(2)D-3 docking model was firmly substantiated by mutation analysis. Using this VDR model, the structure-function relationship of highly potent vitamin D analogs was discussed.

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Documento generato il 26/09/20 alle ore 12:12:27