Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1alpha,25(OH)2-vitamin D3 signaling.
Structural and molecular studies have shown that the vitamin D receptor (VDR) mediates 1alpha,25(OH)2-vitamin D3 gene transactivation. Recent evidence indicates that both VDR and the estrogen receptor are localized to plasma membrane caveolae and are required for initiation of nongenomic (NG) responses. Computer docking of the NG-specific 1alpha,25(OH)2-lumisterol to the VDR resulted in identification of an alternative ligand-binding pocket that partially overlaps the genomic pocket described in the experimentally determined x-ray structure. Data obtained from docking five different vitamin D sterols in the genomic and alternative pockets were used to generate a receptor conformational ensemble model, providing an explanation for how VDR and possibly the estrogen receptor can have genomic and NG functionality. The VDR model is compatible with the following: (i) NG chloride channel agonism and antagonism; (ii) variable ligand-stabilized trypsin digest banding patterns; and (iii) differential transcriptional activity, employing different VDR point mutants and 1alpha,25(OH)2-vitamin D3 analogs.
Department of Biochemistry, University of California, Riverside, CA 92521, USA.
Mathew T
MT
Mizwicki
Don
D
Keidel
Craig M
CM
Bula
June E
JE
Bishop
Laura P
LP
Zanello
Jean-Marie
JM
Wurtz
Dino
D
Moras
Anthony W
AW
Norman
D001665:Binding Sites; D002117:Calcitriol / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry* / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D017354:Point Mutation; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D018118:Chloride Channels; D008024:Ligands; D018167:Receptors, Calcitriol; D002117:Calcitriol