Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain

Keiko Yamamoto, Hiroyuki Masuno, Mihwa Choi, Kinichi Nakashima, Tetsuya Taga, Hiroshi Ooizumi, Kazuhiko Umesono, Wanda Sicinska, Janeen VanHooke, Hector F. DeLuca, Sachiko Yamada

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Abstract

The ligand binding domain of the human vitamin D receptor (VDR) was modeled based on the crystal structure of the retinoic acid receptor. The ligand binding pocket of our VDR model is spacious at the helix 11 site and confined at the β-turn site. The ligand 1α,25-dihydroxyvitamin D3 was assumed to be anchored in the ligand binding pocket with its side chain heading to helix 11 (site 2) and the A-ring toward the β-turn (site 1). Three residues forming hydrogen bonds with the functionally important 1α- and 25-hydroxyl groups of 1α,25-dihydroxyvitamin D3 were identified and confirmed by mutational analysis: the 1α-hydroxyl group is forming pincer- type hydrogen bonds with S237 and R274 and the 25-hydroxyl group is interacting with H397. Docking potential for various ligands to the VDR model was examined, and the results are in good agreement with our previous three- dimensional structure-function theory.

Original languageEnglish
Pages (from-to)1467-1472
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number4
DOIs
Publication statusPublished - Feb 15 2000
Externally publishedYes

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