Three-dimensional model of the ligand binding domain of the nuclear receptor for 1alpha,25-dihydroxy-vitamin D(3).
A three-dimensional model for residues 142-427 of the ligand binding domain (LBD) of the human nuclear receptor for 1alpha, 25-dihydroxy-vitamin D(3) [VDR] has been generated based on the X-ray crystallographic atomic coordinates of the LBD of the rat alpha1 thyroid receptor (TR). The VDR LBD model is an elongated globular shape comprised of an antiparallel alpha-helical triple sandwich topology, made up of 12 alpha-helical elements linked by short loop structures; collectively these structural features are similar to the characteristic secondary and tertiary structures for six nuclear receptors with known X-ray structures. The model has been used to describe the interaction of the conformationally flexible natural hormone, 1alpha,25-dihydroxy-vitamin D(3) [1alpha, 25(OH)(2)D(3)], and a number of related analogs with the VDR LBD. The optimal orientation of the 1alpha,25(OH)(2)D(3) in the LBD is with its A-ring directed towards the interior and its flexible side chain pointing towards and interacting with helix-12, site of the activation function-2 domain (AF-2) of the VDR. Mapping of four natural and one experimental point mutations of the VDR LBD, which result in ligand-related receptor dysfunction, indicates the close proximity of these amino acids to the bound ligand.
Department of Biochemistry, University of California-Riverside, Riverside, California 92521, USA. Norman@ucrac1.ucr.edu
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Norman
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Adams
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Collins
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Okamura
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Fletterick
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011487:Protein Conformation; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry
D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D