Vitamin D Receptor Related Drug Discovery Products

Vitamin D Receptors (VDRs) constitute a class of nuclear receptors that modulate gene expression in response to the biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), also known as calcitriol. VDRs play pivotal roles in various physiological processes, including calcium and phosphate homeostasis, bone mineralization, immune modulation, and cellular differentiation and proliferation. Given their wide-ranging influence on cellular function and human health, VDRs represent promising drug targets for a variety of clinical conditions.

Fig.1 VDR bound to DNA, with vitamin D shown in magenta. (Goodsell, 2012)

To meet the needs of drug discovery, Creative Biolabs can provide a wide variety of vitamin D receptor related products:

• Vitamin D Receptor Assays
• Membrane Protein Tools

Overview of Vitamin D Receptor-related Proteins

VDR-A (full-length VDR): The full-length VDR, also known as VDR-A, is the canonical and most widely studied isoform of the VDR protein. It comprises 427 amino acids and consists of several functional domains, including the N-terminal DNA-binding domain (DBD), the C-terminal ligand-binding domain (LBD), and a hinge region connecting the two domains. VDR-A is predominantly responsible for the genomic actions of 1,25(OH)2D3, regulating gene expression by binding to VDREs in target genes.

VDR-B: VDR-B is an isoform generated by the inclusion of an additional exon, which encodes a 50-amino acid insert in the N-terminal DBD. This insert modulates the DNA-binding properties of the VDR-B isoform, potentially altering its target gene selectivity and transcriptional regulation. VDR-B expression has been reported in various tissues, including bone and immune cells, suggesting a role in bone metabolism and immune function.

VDR-C: VDR-C is a truncated isoform that lacks the C-terminal LBD, rendering it unable to bind to 1,25(OH)2D3. This isoform acts as a dominant-negative regulator of the full-length VDR-A by competing for the formation of VDR-RXR heterodimers and VDRE binding. VDR-C has been identified in several tissues, such as the colon, kidney, and immune cells, implicating it in the regulation of diverse physiological processes.

VDR-D: VDR-D is another truncated isoform generated by alternative splicing, which removes part of the LBD, rendering it incapable of binding to 1,25(OH)2D3. The functional implications of VDR-D remain poorly understood, but its expression has been detected in various tissues, such as skin, prostate, and immune cells.

NR2I1 (Nuclear Receptor Subfamily 2 Group I Member 1): NR2I1, also known as testicular receptor 2 (TR2), is a nuclear receptor that shares structural similarities with VDR. While the specific biological functions and ligands of NR2I1 remain to be elucidated, it has been suggested to play a role in male fertility and embryonic development.

NR2I2 (Nuclear Receptor Subfamily 2 Group I Member 2): NR2I2, also referred to as testicular receptor 4 (TR4), is another member of the nuclear receptor family with structural similarities to VDR. Like NR2I1, the specific functions and ligands of NR2I2 are not fully understood; however, it has been implicated in various physiological processes, including spermatogenesis, lipid metabolism, and neurological development.

NR2I3 (Nuclear Receptor Subfamily 2 Group I Member 3): NR2I3, commonly known as the photoreceptor cell-specific nuclear receptor (PNR), is a nuclear receptor predominantly expressed in the retina. NR2I3 is involved in the regulation of photoreceptor development and maintenance. Although NR2I3 shares structural similarities with VDR, its specific ligands and interactions with other nuclear receptors remain to be elucidated.

Fig.2 The metabolic pathway for vitamin D. (Chritakos, 2015)

Vitamin D Receptor Drug Discovery

Given the pleiotropic effects of VDR signaling on human health, modulation of VDR activity presents a promising avenue for therapeutic intervention in a range of pathological conditions. Potential applications include the treatment of bone and mineral disorders, such as osteoporosis and secondary hyperparathyroidism, as well as immune-mediated diseases, including autoimmune disorders and cancer. The development of VDR-targeted therapies requires a deep understanding of the molecular mechanisms governing VDR action, the identification of tissue-specific and context-dependent VDR functions, and the optimization of ligand selectivity and pharmacokinetic properties. Such knowledge will facilitate the design of novel VDR agonists, antagonists, or selective modulators that exhibit improved efficacy, safety, and tolerability profiles, ultimately leading to more effective therapeutic options for patients.

Fig.3 Anticancer properties of vitamin D. (Jeon, 2018)

References

1. Goodsell, D.S. Vitamin D receptor. RCSB PDB. 2012.
2. Chritakos, S.; et al. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiological Reviews. 2015, 96(1): 365-408.
3. Jeon, SM.; Shin, EA. Exploring vitamin D metabolism and function in cancer. Experimental & Molecular Medicine. 2018, 50: 1-14.