Previous Seminars
NICR Seminar - Prof Richard Bayliss
- Venue: Paul O'Gorman Building Seminar Room
- Start: Mon, 20 Mar 2017 13:00:00 GMT
- End: Mon, 20 Mar 2017 14:00:00 GMT
Prof Richard Bayliss of the University of Leeds aims to resolve the workings of the mitotic spindle at the molecular level, and to develop novel cancer drugs that target malfunctioning spindles.
Title: Stabilisation of Myc by Aurora-A as a therapeutic cancer target.
Synopsis: 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 instrinsically 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 infrequent and limited to short fragments. For example, the C-terminal, DNA-binding region of Myc forms a basic helix-loop-helix (bHLH) structure in complex with Max. We recently determined the crystal structure of Aurora-A kinase domain bound to fragment of the transactivation domain of N-Myc spanning twenty-eight amino acids. The structure reveals a helical conformation of N-Myc between two tryptophan resiudes that recognize the surface of Aurora-A. Aurora-A has a role independent of its catalytic activity, acting as a molecular scaffold upon which N-Myc becomes ordered. The binding site for N-Myc on Aurora-A is disrupted by certain ATP-competitive inhibitors of Aurora-A, such as MLN8237 and CD532. This 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, and which might be developed into Myc inhibitors for the treatment of cancer.
Hosted by Jane Endicott.