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标题：Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors
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作者：Mark W. Richards ; Selena G. Burgess ; Evon Poon 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：13726-13731
DOI：10.1073/pnas.1610626113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceElevated levels of N-Myc protein (the product of the MYCN oncogene) drive cancers such as neuroblastoma. Accumulation of N-Myc in these cancer cells depends upon the formation of a complex with the protein kinase Aurora-A in which the N-Myc is not properly degraded. We mapped the region of N-Myc that interacts with Aurora-A and determined the molecular structure of the complex. Because this region also interacts with cellular machinery that targets N-Myc for degradation, we sought to understand the mechanism by which N-Myc stabilizes Aurora-A. The structure explains how compounds that induce distorted conformations of Aurora-A are able to disrupt the interaction with N-Myc. This understanding may provide a basis for designing better compounds that work in this way for the treatment of neuroblastoma. Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turnover by the ubiquitin-proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by the E3 ubiquitin ligase SCFFbxW7. However, N-Myc protein (the product of the MYCN oncogene) is stabilized in neuroblastoma by the protein kinase Aurora-A in a manner that is sensitive to certain Aurora-A-selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCFFbxW7. We determined the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72-[IMG]f1.gif" ALT="A" BORDER="0"> resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with the binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCFFbxW7 to disfavor the generation of Lys48-linked polyubiquitin chains.
关键词：structural biology ; Aurora-A kinase ; protein–protein interaction ; Myc ; neuroblastoma