# The N-Myc MB0-MBI region interacts specifically and dynamically with the N-lobe of Aurora kinase A

## TL;DR

The study shows how the disordered N-Myc protein interacts with Aurora kinase A to promote its activation, offering a potential target for treating neuroendocrine tumors.

## Contribution

The paper reveals a dynamic and inhibitable interaction between N-Myc and Aurora A's N-lobe, governed by aromatic clusters in conserved motifs.

## Key findings

- N-Myc interacts with Aurora A's N-lobe through multiple binding sites in a dynamic mode.
- Aromatic clusters in the MB0 and MBI motifs of N-Myc are critical for the interaction.
- The small-molecule AurkinA can inhibit the N-Myc–Aurora A interaction, suggesting therapeutic potential.

## Abstract

The intrinsically disordered MYC proteins are master regulators of cellular growth and function, but when deregulated they become cancer drivers. MYC-protein interactions are key to oncogenesis, and while disrupting such interactions would be of significant therapeutic benefit, the intrinsically disordered properties of MYC have dramatically hampered their characterization. Here, we apply an integrated structural biology approach to describe the structure and dynamics of the N-Myc–Aurora A complex, which is critical in neuroendocrine tumor progression. We reveal a functional interaction where multiple binding sites on N-Myc interact with the Aurora A N-lobe. The interaction is governed by aromatic clusters within the conserved MB0 and MBI motifs in N-Myc that interact with Aurora A in a dynamic binding mode that allosterically promotes kinase activation. We show that N-Myc binding to the Aurora A N-lobe can be inhibited by the small-molecule AurkinA, providing opportunity for therapeutical strategies to disrupt this interaction.

The authors reveal how the intrinsically disordered oncoprotein N-Myc dynamically interacts with Aurora kinase A in an inhibitable binding mode that allosterically promotes its activation, offering opportunities to restrict neuroendocrine tumor growth.