Three-dimensional structure-function relationship of vitamin D and vitamin D receptor model

Sachiko Yamada, Keiko Yamamoto, Hiroyuki Masuno, Mihwa Choi

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

On the basis of conformational analysis of the vitamin D side chain and studies using conformationally restricted synthetic vitamin D analogs, we have suggested the active space region concept of vitamin D: The vitamin D side-chain region was grouped into four regions (A, G, EA and EG) and the A and EA regions were suggested to be important for vitamin D actions. We extended our theory to known highly potent vitamin D analogs and found a new region F. The analogs which occupy the F region have such modifications as 22-oxa, 22-ene, 16-ene and 18-nor. Altogether, the following relationship between the space region and activity was found: Affinity for vitamin D receptor (VDR), EA > A > F > G > EG; Affinity for vitamin D binding protein (DBP), A > G,EA,EG; Target gene transactivation, EA > F > A > EG > EG; Cell differentiation, EA > F > A > EG > EG; Bone calcium mobilization, EA > GA > F > EG; Intestinal calcium absorption, EA = A > G > EG. We modeled the 3D structure of VDR-LBD (ligand binding domain) using hRARγ as a template, to develop our structure-function theory into a theory involving VDR. 1α,25(OH)2D3 was docked into the ligand binding pocket of the VDR with the side chain heading the wide cavity at the H-11 site, the A-ring toward the narrow β-turn site, and the β-face of the CD ring facing H3. Amino acid residues forming hydrogen bonds with the 1α- and 25-OH groups were specified: S237 and R274 forming a pincer type hydrogen-bond for the 1α-OH and H397 for the 25-OH. Mutants of several amino acid residues that are hydrogen-bond candidates were prepared and their biologic properties were evaluated. All of our mutation results together with known mutation data support our VDR model docked with the natural ligand.

Original languageEnglish (US)
Pages (from-to)177-187
Number of pages11
JournalSteroids
Volume66
Issue number3-5
DOIs
StatePublished - May 1 2001
Externally publishedYes

Keywords

  • Homology modeling
  • Nuclear receptor
  • Structure-function relationship
  • Vitamin D

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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