Vitamin D receptor 2016: novel ligands and structural insights

ABSTRACT

Introduction: Vitamin D₃ activates via its hormonal form 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃), the transcription factor vitamin D receptor (VDR). VDR is expressed in most human tissues and has more than 1,000 target genes. Thus, 1α,25(OH)₂D₃ and its synthetic analogs have a broad physiological impact. The crystal structures of the VDR ligand-binding domain (LBD), and its various ligands, allows further the understanding of the receptor’s molecular actions.

Areas covered: We discuss the most important novel VDR ligands and the further insight derived from new structural information on VDR.

Expert opinion: There is an increasing appreciation of the impact of vitamin D and its receptor VDR not only in bone biology, but also for metabolic diseases, immunological disorders, and cancer. Detailed structural analysis of the interaction of additional novel ligands with VDR highlight helices 6 and 7 of the LBD as being most critical for stabilizing the receptor for an efficient interaction with co-activator proteins, i.e. for efficient agonistic action. This permits the design of even more effective VDR agonists. In addition, chemists took more liberty in replacing major parts of the 1α,25(OH)₂D₃ molecule, such as the A- and CD-rings or the side chain, with significantly different structures, such as carboranes, and still obtained functional VDR agonists.

KEYWORDS:

• Bile acids
• crystal structure
• vitamin D
• vitamin D analogs
• vitamin D receptor

Article highlights

• Vitamin D is essential for the maintenance of health, such as prevention of bone disorders, muscle weakness, cancer and autoimmune diseases. Thus synthetic vitamin D analogs have a broad therapeutic potential.

• The number of crystal structures of the VDR-LBD with different natural and synthetic ligands is constantly increasing. Detailed structural analysis of the latest VDR crystal structures indicated that helices 6 and 7 of the LBD are most critical for the stabilizing the receptor for an efficient interaction with co-activator proteins.

• Major parts of the 1α,25(OH)₂D₃ molecule, such as the A- and CD-rings or the side chain, were replaced with significantly different structures, such as carboranes, and still functional VDR agonists were obtained.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the Academy of Finland (Biotieteiden ja Ympäristön Tutkimuksen Toimikunta, 267067), the Juselius Foundation, and Xunta de Galicia (GPC2014/001).