2021年7月26日
Mechanism of Vitamin D Receptor Ligand-Binding Domain Regulation Studied by gREST Simulations.
Journal of chemical information and modeling
- ,
- ,
- ,
- 巻
- 61
- 号
- 7
- 開始ページ
- 3625
- 終了ページ
- 3637
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1021/acs.jcim.1c00534
The vitamin D receptor ligand-binding domain (VDR-LBD) undergoes conformational changes upon ligand binding. In this nuclear receptor family, agonistic or antagonistic activities are controlled by the conformation of the helix (H)12. However, all crystal structures of VDR-LBD reported to date correspond to the active H12 conformation, regardless of agonist/antagonist binding. To understand the mechanism of VDR-LBD regulation structurally, conformational samplings of agonist- and antagonist-bound rat VDR-LBD were performed using the generalized replica exchange with solute tempering (gREST) method. The gREST simulations demonstrated different structural responses of rat VDR-LBD to agonist or antagonist binding, whereas in conventional molecular dynamics simulations, the conformation was the same as that of the crystal structures, regardless of agonist/antagonist binding. In the gREST simulations, a spontaneous conformational change of H12 was observed only for the antagonist complex. The different responses to agonist/antagonist binding were attributed to hydrophobic core formation at the ligand-binding pocket and cooperative rearrangements of H11. The gREST method can be applied to the examination of structure-activity relationships for multiple VDR-LBD ligands.
- ID情報
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- DOI : 10.1021/acs.jcim.1c00534
- PubMed ID : 34189910