Vitamin D Receptor Assays
Overview of Vitamin D Receptor (VDR)
The VDR belongs to the NR1I family. They play a key role in the biological role of vitamin D. VDR is closely related to the expression of numerous genes involved in physiological activities. Furthermore, activation of VDR signaling is involved in many processes, including immune responses, calcium and phosphate homeostasis, cellular apoptosis, and immune responses. Notably, VDR is protective against colorectal cancer.
Distributions of VDRs
VDRs are widely distributed in a variety of tissues. VDRs are found in respiratory epithelial cells, reproductive tissues, and immune cells. The tissues with the highest levels of VDR are the intestine, kidney, parathyroid gland, and bone, all of which are involved in the maintenance of calcium homeostasis. VDRs are also present in vascular smooth muscle, endothelial, and cardiomyocytes and may have implications for cardiovascular disease.
Fig.1. Vitamin D signaling pathway. (Kim, 2020)
Mechanisms of VDRs
There are several different VDR-like receptors, and the relevant information is summarized in the table below.
| Receptor | Gene | Mechanism | Agonists | Antagonists |
| VDR | VDR |
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Published Data
| Paper Title | Mechanism of Vitamin D Receptor Ligand-Binding Domain Regulation Studied by gREST Simulations |
| Journal | Journal of Chemical Information and Modeling |
| Published | 2021 |
| Abstract | The VDR ligand-binding domain (VDR-LBD) undergoes a conformational change following ligand binding. In this family of nuclear receptors, the agonistic or antagonistic activities are closely related to the conformation of the helix (H)12. However, all current VDR-LBD crystal structures correspond to the active H12 conformation. To structurally elucidate the mechanism of VDR-LBD regulation, the generalized replica exchange with solute tempering (gREST) method was used to perform conformational sampling of agonist- and antagonist-bound rat VDR-LBD. gREST simulations demonstrate distinct structural responses of rat VDR-LBDs to agonist or antagonist binding. In gREST simulations, spontaneous conformational changes of H12 were only observed for the antagonist complex. Differential responses to agonist/antagonist binding are associated with the formation of a hydrophobic core in the ligand-binding pocket and the coordinated rearrangement of H11. The gREST method plays a crucial role in examining the structure-activity relationship of multiple VDR-LBD ligands. |
| Result |
This article elucidated that agonist and antagonist complexes exhibited distinct structural responses depending on their activity through the gREST approach. Although the initial structure was the active crystal structure, the antagonist complex exhibited a spontaneous conformational change, with the position of H12 deviating from its canonical position. Conversely, in agonist complexes, the active conformation was stable. In addition, the article proposed that gREST simulations contributed to capturing plausible conformations to explain both excitation and antagonism.
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Fig.2. Correlations between the rmsd of H12 and the angle of the kink. (Ekimoto, 2021)
References
- Kim, H. A.; et al. Vitamin D deficiency and the risk of cerebrovascular disease. Antioxidants. 2020; 9(4): 327.
- Ekimoto, T.; et al. Mechanism of Vitamin D Receptor Ligand-Binding Domain Regulation Studied by gREST Simulations. Journal of Chemical Information and Modeling. 2021; 61(7): 3625-3637.
