The Myc proteins comprise a family of ubiquitous regulators of gene expression implicated in over half of all human cancers. They interact with a large number of other proteins, such as transcription factors, chromatin-modifying enzymes and kinases. Remarkably, few of these interactions have been characterized structurally. This is at least in part due to the intrinsically disordered nature of Myc proteins, which adopt a defined conformation only in the presence of binding partners. Owing to this behaviour, crystallographic studies on Myc proteins have been limited to short fragments in complex with other proteins. Most recently, we determined the crystal structure of Aurora-A kinase domain bound to a 28-amino acid fragment of the N-Myc transactivation domain. The structure reveals an α-helical segment within N-Myc capped by two tryptophan residues that recognize the surface of Aurora-A. The kinase domain acts as a molecular scaffold, independently of its catalytic activity, upon which this region of N-Myc becomes ordered. The binding site for N-Myc on Aurora-A is disrupted by certain ATP-competitive inhibitors, such as MLN8237 (alisertib) and CD532, and explains how these kinase inhibitors are able to disrupt the protein–protein interaction to affect Myc destabilization. Structural studies on this and other Myc complexes will lead to the design of protein–protein interaction inhibitors as chemical tools to dissect the complex pathways of Myc regulation and function, which may be developed into Myc inhibitors for the treatment of cancer.
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Cover Image
Cover Image
An artistic model of the ‘molecular scissor’ ADAM10 (displayed in orange) at the cell surface, shown cleaving one of its substrates (green). ADAM10 is regulated by one of six TspanC8 tetraspanins (displayed in white or blue). The TspanC8s have distinct mechanisms of binding to ADAM10 and appear to dictate its substrate specificity. For more information, please see pages 719–730 in this issue of the Biochemical Society Transactions. Designer: Justyna Szyroka Artist: Eduardo Oliveira - Graphics Designer and Animator. Image kindly provided by Michael G Tomlinson.
A moving target: structure and disorder in pursuit of Myc inhibitors
Richard Bayliss, Selena G. Burgess, Eoin Leen, Mark W. Richards; A moving target: structure and disorder in pursuit of Myc inhibitors. Biochem Soc Trans 15 June 2017; 45 (3): 709–717. doi: https://doi.org/10.1042/BST20160328
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