... understanding life in molecular detail

Prof Richard Bayliss

Structural biology, protein kinases, cancer, drug discovery

My team studies the molecular structures and interactions of proteins using structural, cell, chemical and computational biology approaches. We work towards understanding the molecular mechanisms that underpin cellular functions and how these events are altered in diseases such as cancer, cystic kidney disease and microcephaly. In partnership with other scientists, we develop precision drugs that are tailored to individual proteins.

Current major projects include:
  • Microtubule regulation and cell cycle
  • Structure and function of protein kinases
  • Cancer signalling pathways
  • Precision drug discovery

1. Microtubules and cell cycle

Microtubules are dynamic structures that form part of the cellular cytoskeleton. The functions of microtubules vary from cell type to cell type these roles change as the cell cycle progresses. Microtubules form the core of the primary cilium, a signalling organelle found in many cell types. Defects in the primary cilium may give rise to a number of diseases, such as polycystic kidney disease, which are collectively termed ciliopathies. During mitosis, microtubules form the bipolar spindle structure that carries out chromosome division. Errors in this process lead to aneuploidy, chromosomal instability and supernumerary centrosomes, which are common features of tumour cells and arguably drivers of cancer. Our research is focussed on the regulation of microtubules in processes that are implicated in human diseases. One of our projects in this area, funded by BBSRC, aims to resolve the intermicrotubule bridge structures that reinforce the mitotic spindle. The shortest bridges are formed by the clathrin/TACC3/ch-TOG (CTC) complex, assembly of which is controlled by the protein kinase Aurora-A. We recently identified a region of TACC3 that binds and activates Aurora-A, adjacent to the site on TACC3 phosphorylated by Aurora-A (Burgess, PLOS Genetics 2015). 

2. Protein kinases
Protein kinases are commonly mutated or otherwise dysregulated in cancer and inhibitors of protein kinases such as imatinib and crizotinib are key therapeutic drugs. Patients treated with kinase inhibitors inevitably relapse due to kinase overexpression, mutation or the activation of bypass pathways, usually involving other kinases. Combinations of kinase inhibitors might address this issue, but combining these drugs safely and effectively is a challenge. Our research aims to determine the structural mechanisms that underpin kinase regulation and to develop new kinase inhibitors suitable for combination therapies as potential cancer therapeutics. We recently resolved the allosteric mechanism by which the non-catalytic, C-terminal domain (CTD) of NEK9 activates NEK7 (Haq, Nat. Comm. 2015) and showed that IRE1 is regulated through a similar mechanism (Joshi, Oncotarget 2015).

3. Cancer signalling
Lung cancer patients who harbor EML4-ALK fusions initially respond to ALK inhibitors such as crizotinib, but inevitably relapse. We are investigating the contribution of the EML4 part of the fusion in oncogenic signaling and as a target for therapeutics. Using protein crystallography, we determined the structure of the trimerization domain of EML4, which is essential for oncogenic ALK signaling (Richards, Biochem J. 2015). We also determined the structure of the TAPE domain of the related protein EML1, resulting in a molecular basis for the sensitivity of EML4-ALK fusions to Hsp90 inhibition (Richards, PNAS 2014). These findings will be applied to the development of new EML4-ALK inhibitors and extended to studies on other kinase fusions.

4. Drug discovery
Modern approaches to canner drug discovery harness our knowledge of the molecular and genetic basis of disease to develop novel precision drugs that target cancer proteins specifically. Molecular analysis enables doctors to identify which cancer proteins are present in each patient. Personalised medicine, in which therapy is tailored to an individual patient, is revolutionising the treatment of cancer. We have assisted in the development of inhibitors of the protein kinases Aurora-A, NEK2 and IRE1 and have ongoing collaborations on many other targets.

Detailed research programme                  Close ▲

Professor of Molecular Medicine
BA (Cambridge) PhD (Cambridge)

Royal Society Research Fellow, Institute of Cancer Research, 2006-2011
Reader in Structural Biology, University of Leicester, 2011-2014
Professor of Molecular Medicine, University of Leicester, 2014-2015

Astbury 6.108a
School of Molecular and Cellular Biology
0113 3439919

Selected Publications

  1. Richards MW, Burgess SG, Poon E, Carstensen A, Eilers M, Chesler L, Bayliss R Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. Proc Natl Acad Sci U S A 113 13726-13731, 2016 DOI:10.1073/pnas.1610626113

  2. Haq T, Richards MW, Burgess SG, Gallego P, Yeoh S, O'Regan L, Reverter D, Roig J, Fry AM, Bayliss R Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization Nature Communications 6, 2015 DOI:10.1038/ncomms9771

  3. Rogerson DT, Sachdeva A, Wang K, Haq T, Kazlauskaite A, Hancock SM, Huguenin-Dezot N, Muqit MMK, Fry AM, Bayliss R, Chin JW Efficient genetic encoding of phosphoserine and its nonhydrolyzable analog Nature Chemical Biology 11 496-503, 2015 DOI:10.1038/nchembio.1823

  4. Richards MW, Edward EW, Rennalls LP, Busacca S, O'Regan L, Fry AM, Fennell DA, Bayliss R Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypicalβ-propeller domain Proceedings of the National Academy of Sciences of the United States of America 111 5195-5200, 2014 DOI:10.1073/pnas.1322892111