title: Vitamin D receptor 2016: novel ligands and structural insights.
abstract: Vitamin D3activates 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)2D3and 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)2D3molecule, such as the A- and CD-rings or the side chain, with significantly different structures, such as carboranes, and still obtained functional VDR agonists.
authors.affiliation: a Departamento de Química Fundamental, Facultad de Ciencias , Universidade da Coruña , Coruña , Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Maestro
authors.affiliation: b School of Pharmacy, Institute of Biopharmacy , University of Eastern Finland , Kuopio , Finland.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Molnár
authors.affiliation: c Departamento de Química Orgánica, Facultad de Química , Universidad de Santiago , Santiago de Compostela , Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mouriño
authors.affiliation: d School of Medicine, Institute of Biomedicine , University of Eastern Finland , Kuopio , Finland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Carlberg
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002762:Cholecalciferol / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy / Q000473:pathology; D008024:Ligands; D008659:Metabolic Diseases / Q000188:drug therapy / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010330:Patents as Topic; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; D002762:Cholecalciferol; D002117:Calcitriol
keywords: Bile acids; crystal structure; vitamin D; vitamin D analogs; vitamin D receptor