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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月24日

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  • Johanna Hultman,
  • Vivian Morad,
  • Eliane Tanner,
  • Tristan M. G. Kenney,
  • Zuzanna Pietras,
  • Lalit Pramod Khare,
  • Dean Derbyshire,
  • Diana Resetca,
  • Cheryl H. Arrowsmith,
  • Daniel Aili,
  • Simon Ekström,
  • Linda Z. Penn,
  • Björn Wallner,
  • Alexandra Ahlner,
  • Maria Sunnerhagen

摘要

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.