Bayliss, R orcid.org/0000-0003-0604-2773, Burgess, SG, Leen, E et al. (1 more author) (2017) A moving target: structure and disorder in pursuit of Myc inhibitors. Biochemical Society Transactions, 45 (3). pp. 709-717. ISSN 0300-5127
Abstract
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. Due 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 a-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 effect 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017, The Author(s). This is an author produced version of a paper published in Biochemical Society Transactions. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 20 Apr 2017 14:49 |
Last Modified: | 15 Jun 2018 00:38 |
Status: | Published |
Publisher: | Portland Press |
Identification Number: | 10.1042/BST20160328 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:115221 |