Two-dimensional alanine scanning mutational analysis of the interaction between the vitamin D receptor and its ligands: studies of A-ring modified 19-norvitamin D analogs

The Journal of Steroid Biochemistry and Molecular Biology
Masato ShimizuSachiko Yamada

Abstract

To clarify the structure-function relationship (SFR) of vitamin D analogs in terms of their interaction with the vitamin D receptor (VDR), we have proposed a new approach, two-dimensional alanine scanning mutational analysis (2D-ASMA). In this paper, attention was focused on the interactions around the A-ring of vitamin D. For this purpose, we synthesized four new 2-substituted 19-norvitamin D derivatives (3-6). The VDR affinity (3-6: 1, 5, 2 and 1/140, respectively) and transcriptional activity (3-6: 10, 30, 2 and 0.3, respectively) of the four compounds were evaluated relative to 1,25-(OH)(2)D(3) (5) (normalized to 1). Then, the transcriptional activities of wild-type and 18 mutant VDRs induced by the four compounds (3-6) were investigated. The results of this 18 x 4 2D-ASMA were presented as a patch table, and the effects of the mutations were analyzed in comparison with the natural hormone (1) and 2-methylene-19-nor-20-epi-1,25-(OH)(2)D(3) (2MD, 2). Of the four A-ring analogs, the 2alpha-hydroxyethoxy derivative (3) showed striking differences in the pattern on the patch table. From the results, we suggest a docking mode of this compound (3) in which the A-ring adopts the alpha conformation.

References

Dec 15, 1995·Cell·D J MangelsdorfR M Evans
May 7, 1999·Bioorganic & Medicinal Chemistry Letters·K YamamotoS Yamada
Mar 4, 2000·Proceedings of the National Academy of Sciences of the United States of America·K YamamotoS Yamada
Jun 1, 2000·Current Pharmaceutical Design·S YamadaH Masuno
Jun 29, 2000·Annual Review of Biochemistry·R V WeathermanT S Scanlan
May 10, 2001·Proceedings of the National Academy of Sciences of the United States of America·G Tocchini-ValentiniD Moras
Jun 27, 2001·Bioorganic & Medicinal Chemistry·M ChoiS Yamada
Oct 11, 2002·Proceedings of the National Academy of Sciences of the United States of America·Nirupama K ShevdeHector F DeLuca
Nov 9, 2002·Medicinal Research Reviews·Sachiko YamadaKeiko Yamamoto

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