Differing shapes of 1 alpha,25-dihydroxyvitamin D3 function as ligands for the D-binding protein, nuclear receptor and membrane receptor: a status report.
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 <0.1% of the activity of 1 alpha,25(OH)2D3 in regulating gene transcription.
Norman
A W
AW
Department of Biochemistry, University of California, Riverside, USA.
Bishop
J E
JE
Collins
E D
ED
Seo
E G
EG
Satchell
D P
DP
Dormanen
M C
MC
Zanello
S B
SB
Farach-Carson
M C
MC
Bouillon
R
R
Okamura
W H
WH
D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D009687:Nuclear Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000145:classification / Q000302:isolation & purification / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D008565:Membrane Proteins; D009687:Nuclear Proteins; D018167:Receptors, Calcitriol; D002117:Calcitriol