Rational design of vitamin D3 analogues which selectively restore activity to a vitamin D receptor mutant associated with rickets |
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Authors: | Swann Steve L Bergh Joel J Farach-Carson M Cindy Koh John T |
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Institution: | Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA. |
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Abstract: | formula: see text] Vitamin D3-resistant rickets (VDRR) is associated with mutations to the Vitamin D receptor (VDR) which effect ligand-dependent transactivation. Some VDRR associated mutants directly disrupt ligand binding. Using the reported VDR-1,25-dihydroxy vitamin D3 (1,25(OH)2D3) cocrystal structure, three 1,25(OH)2D3 analogues were designed to uniquely complement the rickets associated mutant VDR(Arg274-->Leu). The three analogues were 17 to 286 times more potent than 1,25(OH)2D3 with the mutant in cell-based assays and did not substantially activate cellular calcium influx. |
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