Differing shapes of 1 alpha,25-dihydroxyvitamin D3 function as ligands for the D-binding protein, nuclear receptor and membrane receptor: a status report

• Published in: The Journal of steroid biochemistry and molecular biology 1996-01, Vol.56 (1-6 Spec No), p.13-22
• Main Authors: Norman, A W, Bishop, J E, Collins, E D, Seo, E G, Satchell, D P, Dormanen, M C, Zanello, S B, Farach-Carson, M C, Bouillon, R, Okamura, W H
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Calcitriol - chemistry; Calcitriol - metabolism; Humans; Ligands; Membrane Proteins - chemistry; Membrane Proteins - isolation & purification; Membrane Proteins - metabolism; Models, Biological; Models, Molecular; Molecular Conformation; Nuclear Proteins - chemistry; Nuclear Proteins - isolation & purification; Nuclear Proteins - metabolism; Protein Binding; Protein Conformation; Receptors, Calcitriol - chemistry; Receptors, Calcitriol - classification; Receptors, Calcitriol - isolation & purification; Receptors, Calcitriol - metabolism; Structure-Activity Relationship
• ISSN: 0960-0760
• DOI: 10.1016/0960-0760(95)00219-7

1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] is the principal mediator of a wide array of biological responses through the far reaching network of the vitamin D endocine system (VDE). The steroid hormone 1 alpha,25(OH)2D3 is delivered to the various target organs of the VDE via a specific plasma transport protein, the vitamin D binding protein (DBP). Also 1 alpha,25(OH)2D3 is known to initiate biological responses through a nuclear receptor, the nVDR (50 kDa) which regulates selected gene transcription and, in addition in some target tissues, through a second receptor located in the cell membrane, the mVDR (approximately 60 kDa), which is linked to protein kinase C and/or voltage-gated Ca2+ channels so as to generate biological responses very rapidly. 1 alpha,25(OH)2D3 as a ligand is unusually conformationally flexible due to the eight carbon side chain, the seco B-ring which permits rotation about the 6-7 single carbon bond, and the A-ring which undergoes chair-chair conformational interconversion characteristic of cyclohexane rings. This paper reviews the evidence that different shapes of the 1 alpha,25(OH)2D3 satisfy the optimal requirements of the ligand binding domains of the DBP, nVDR and mVDR. The presence of a relatively rigid side chain (composed by the presence of an aromatic ring) enhances ligand interaction 2-3 fold with the DBP, but diminishes ligand affinity for the nVDR by 100 fold. The mVDR responds effectively to analogs of 1 alpha,25(OH)2D3 which are 6-s-cis locked [e.g. 1 alpha,25(OH)2-previtamin D3 or 1 alpha,25(OH)2-provitamin D3], but these same analogs have only 1-2% of the activity of 1 alpha,25(OH)2D3 in regulating gene transcription. Finally the 6-s-trans analog, 1 alpha,25(OH)2-tachysterol3, had