Correlation between secosteroid-induced vitamin D receptor activity in melanoma cells and computer-modeled receptor binding strength

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• 作者：Tae-Kang Kim ; Jin Wang ; Zorica Janjetovic ; Jianjun Chen ; Robert C. Tuckey ; Minh N. Nguyen ; Edith K.Y. Tang ; Duane Miller ; Wei Li ; Andrzej T. Slominski
• 关键词：Secosteroid ; Melanoma ; Vitamin D receptor ; Computer modeling
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2012
• 出版时间：25 September, 2012
• 年：2012
• 卷：361
• 期：1-2
• 页码：143-152
• 全文大小：1714 K

文摘

To define the interaction of novel secosteroids produced by the action of cytochrome P450scc with vitamin D receptor (VDR), we used a human melanoma line overexpressing VDR fused with enhanced green fluorescent protein (EGFP) and tested the ligand induced translocation of VDR from the cytoplasm to the nucleus. Hydroxyderivatives of vitamin D₃ with a full length (D₃) side chain and hydroxy-secosteroids with a shortened side chain (pD) stimulated VDR translocation and inhibited proliferation, however, with different potencies. In general the D₃ were more potent than pD analogues. Molecular modeling of the binding of the secosteroids to the VDR genomic binding pocket (G-pocket) correlated well with the experimental data for VDR translocation. In contrast, docking scores for the non-genomic binding site of the VDR were poor. In conclusion, both the length of the side chain and the number and position of hydroxyl groups affect the activation of VDR by novel secosteroids.