Research Interests

Latest News

 

Congratulations to Dr Tammy Haq on passing her PhD viva!

We have been busy publishing papers - 9 accepted or already published in the first 6 months of this year.

In a recent Oncotarget paper, we report crystal structures of human IRE1, a drug target in myeloma, that provide a basis for structure-guided design of inhibitors.

Building on our 2014 PNAS paper, we describe the structure of the coiled-coil domain of EML4 in Biochemical Journal.

We have made progress on the regulation of mitotic spindle assembly by Aurora-A and Nek6 kinases through the TACC3 and its binding partners, work published in the Journal of Cell Biology, PLOS Genetics and Biology Open.

Nek7 kinase expressed with a genetically-encoded phosphoserine is fully active and no longer requires its activator, Nek9 - published in Nature Chemical Biology.

These studies are the result of enjoyable and productive collaborations with the groups of Andrew Fry (Leicester), Stephen Royle and Anne Straube (Warwick), Fanni Gergely (CRUK Institute, Cambridge), Jason Chin (MRC-LMB, Cambridge), Mark Pfuhl (Kings College London), Isabelle Vernos (CRG, Barcelona) and Ian Collins (Institute of Cancer Research, Sutton).

 

 

Molecular mechanisms of mitosis and cell division


A cell undergoes a spectacular transformation as it enters mitosis, the phase of its existence just before it divides into two daughter cells. The membrane that surrounds its nucleus dissolves, its chromosomes (DNA) condense to form ‘X’ shapes, and its microtubules, which form part of the cell’s internal transport network, re-organise to form the mitotic spindle. The spindle is a molecular machine that ensures that each daughter cell receives the correct amount of DNA. Errors in the spindle’s workings are associated with cancer because they can create large-scale re-arrangements of chromosomes. As well as microtubules, spindles are made up of hundreds of other proteins that work together to minimize errors. We do not understand the individual role of most of these proteins or how they work together to make a spindle. The aim of my research is to resolve the workings of the mitotic spindle at the molecular level, and to develop novel cancer drugs that target malfunctioning spindles.

 

My team uses X-ray crystallography to resolve the position of every atom within the three-dimensional structures of proteins involved in spindle assembly. These structures reveal the workings of the mitotic spindle at the level of individual atoms, and form the basis for interpreting what happens in inaccurate spindle formation. Accurate mitotic spindle assembly requires the regulated activity of many proteins in the cell, in particular enzymes such as kinases. These enzymes are an important part of regulation in the cell because they modify other proteins such as those responsible for building the spindle. The modified proteins have changed properties. In normal cells, the activity of kinases such as Aurora-A that control mitotic spindle assembly is strictly regulated by many other proteins. In cancerous cells, however, the enzymes may be activated erroneously, allowing the cell to divide out of control.

 

Cancer drug discovery

Many of the enzymes involved in spindle assembly are potential drug targets, and my basic research informs the strategy by which they are targeted in the development of cancer drugs. Together with chemistry colleagues from the ICR and Newcastle, my team helps produce compounds that target protein kinases. X-ray crystallography accelerates the design of better drugs because the drug-enzyme structure enables us to see what improvements need to be made.

 

We have thus far focussed our structure-based design approach on two mitotic kinases, Aurora-A and Nek2. Together with colleagues at The Institute of Cancer Research, we have produced selective inhibitors of these two oncology targets. We now aim to investigate how these compounds should be used in the cancer clinic, using the inhibitors as tools to explore cellular pathways that are crucial for cell proliferation and survival.

 

Selected Publications

1. Burgess SG, Peset I, Joseph N, Cavazza T, Vernos I, Pfuhl M, Gergely F, Bayliss R (2015) Aurora-A-dependent control of TACC3 influences the rate of mitotic spindle assembly. PLOS Genetics

2. Rogerson D, Sachdeva A, Wang K, Haq T, Kazlauskaite A, Muqit MMK, Fry AM, Bayliss R, Chin J (2015) Efficient and site-specific incorporation of phosphoserine and its non-hydrolyzable analog into recombinant proteins. Nat. Chem. Biol.

3. O’Regan L, Sampson J, Richards MW, Knebel A, Roth D, Hood FE, Straube A, Royle SJ, Bayliss R, Fry AM (2015) Hsp72 is targeted to the mitotic spindle by Nek6 to promote K-fiber assembly and mitotic progression. J. Cell. Biol.

4. Joshi A, Newbatt Y, McAndrew PC, Stubbs M, Burke R, Richards MW, Caldwell JJ, McHardy T, Collins I, Bayliss R (2015) Molecular mechanisms of human IRE1 activation through dimerization and ligand binding. Oncotarget 5.

 

5. Richards MW, Law EP, Rennalls LP, Busacca S, O'Regan L, Fry AM, Fennell DA, Bayliss R (2014) Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical b-propeller domain. Proc. Natl. Acad. Sci. USA (published online 24th March 2014).

6. Rowan FC, Richards M, Bibby RA, Thompson A, Bayliss R, Blagg J (2013) Insights into Aurora-A Kinase Activation Using Unnatural Amino Acids Incorporated by Chemical Modification. ACS Chem. Bio 8:2184-91.

7. Hood FE, Williams SJ, Burgess SG, Richards MW, Roth D, Straube A, Pfuhl M, Bayliss R, Royle SJ (2013) Coordination of adjacent domains mediates TACC3-ch-TOG-clathrin assembly and mitotic spindle binding. J. Cell. Biol. 202:463-78.

8. Dodson CA, Yeoh S, Haq T, Bayliss R (2013) A Kinetic Test Characterizes Kinase Intramolecular and Intermolecular Autophosphorylation Mechanisms. Sci Signal. 6:ra54.

9. Fry AM, O'Regan L, Sabir SR, Bayliss R (2012) Cell cycle regulation by the NEK family of protein kinases. J. Cell. Sci. 125:4423-33.

10. Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, Moore AS, Kosmopoulou M, Brown N, Sheldrake PW, Bush K, Henley A, Box G, Valenti M, de Haven Brandon A, Raynaud FI, Workman P, Eccles SA, Bayliss R, Linardopoulos S, Blagg J (2012) Optimization of Imidazo[4,5-b]pyridine-Based Kinase Inhibitors: Identification of a Dual FLT3/Aurora Kinase Inhibitor as an Orally Bioavailable Preclinical Development Candidate for the Treatment of Acute Myeloid Leukemia. J. Med. Chem. 55:8721-34.

11. Dodson CA, Bayliss R (2012) Activation of Aurora-A kinase by protein partner binding (TPX2) and phosphorylation are independent and synergistic. J.Biol.Chem. 287:1150-7.

12.  Zalli D, Bayliss R, Fry AM (2012) The Nek8 protein kinase, mutated in the human cystic kidney disease nephronophthisis, is both activated and degraded during ciliogenesis. Hum. Mol. Gen. 21:1155-71.

13. Solanki S, Innocenti P, Mas-Droux C, Boxall K, Barillari C, van Montfort RLM, Aherne GW, Bayliss R, and Hoelder S (2011) Benzimidazole Inhibitors Induce a DFG-Out Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2) without Binding to the Back Pocket and Reveal a Nonlinear Structure−Activity Relationship. J. Med. Chem. 54: 1626-1639.

14. Oberoi J, Richards MW, Crumpler S, Brown N, Blagg, J, Bayliss R (2010) Structural basis of poly(ADP-ribose) recognition by the multi-zinc binding domain of Checkpoint with Forkhead-associated and RING domains (CHFR). J. Biol. Chem. 285: 39348-3935.

15. Dodson CA, Kosmopoulou M, Richards MW, Atrash B, Bavetsias V, Blagg J, Bayliss R (2010) Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design. Biochem. J. 427(1):19-28

16.    Richards MW, O’Regan L, Mas-Droux C, Blot JMY, Cheung J, Hoelder S, Fry AM, Bayliss R (2009) An auto-inhibitory tyrosine motif in the cell cycle-regulated Nek7 kinase is released through binding of Nek9. Mol. Cell. 36(4):560-70

17.     Bayliss R, Harris R, Coutte L, Monier A, Fronzes R, Christie PJ, Driscoll P, Waksman G (2007) NMR Structure of a complex between the VirB9/VirB7 interaction domains of the pKM101 type IV secretion system. Proc. Natl. Acad. Sci. USA 104(5):1673-8

18.  Terradot L, Bayliss R, Oomen C, Leonard G, Baron C, Waksman G (2005) Structures of two core subunits of the bacterial type IV secretion system, VirB8 from Brucella suis and ComB10 from Helicobacter pylori. Proc. Natl. Acad. Sci. USA 102(12):4596-601.

19.  Bayliss R, Sardon T, Vernos I, Conti E (2003) Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol. Cell. 12(4):851-62

20.  Bayliss R, Littlewood T, Stewart M (2000) Structural basis for the interaction between FxFG nucleoporin repeats and Importin-beta in nuclear trafficking. Cell 102(1):99-108

Share this page:

Contact Details

Department of Molecular and Cell Biology

T: +44(0)116 229 7038
E: MolCellBiol@le.ac.uk

Map with link to google maps geotag of Henry Wellcome

Henry Wellcome Building - University of Leicester, Lancaster Rd, LE1 7HB

Postal: Henry Wellcome Building, University of Leicester, Leicester, LE1 7RH

Directions on Arrival to The Henry Wellcome Building

Student complaints procedure

Accessibility

DisabledGo logo

The University of Leicester is committed to equal access to our facilities. DisabledGo has a detailed accessibility guide for the Henry Wellcome Building.