Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Abstract

Significance Elevated 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.