Research

Our group works in the field of chemical biology, applying chemical tools to ask questions about dynamic protein function and small molecule mode of action in live cells and at the molecular level. We work closely with scientists from other disciplines, enabling us to design innovative tools for cell biology and to tackle a wide range of biological questions – from the mechanisms of antibacterial resistance, to how plants regulate growth, and cancer cell signalling pathways.

Our interests include:

  • small molecule mode of action / target identification
  • cell-cell communication e.g. quorum sensing, interkingdom signalling
  • protein post-translational modifications
  • bioorthogonal ligation chemistry
  • activity-based protein profiling
  • photoaffinity labelling
  • mass spectrometry-based proteomics

Cell-cell signalling. We are interested in exploring native small molecule-protein interactions in complex, multispecies biological systems. For example, there is increasing evidence that bacterial and human cells eavesdrop on each other’s cell-cell communications, yet in many cases we do not know how signals are sensed or we lack the tools to understand the mechanisms of sensing.

Target identification methodology. We are developing chemical probes with photo- or chemically-reactive functionalities to stabilise their interactions with protein targets in live cells. We also equip probes with small, minimally disruptive tags, that then act as handles for selective labelling of probe-protein complexes via click chemistry. Click chemistry is very versatile and we can attach fluorophores to visualise proteins, or affinity tags to isolate and identify them by mass spectrometry proteomics.

Protein modification. Proteins are widely modified with small molecules, exerting exquisite and rapid control over protein function. Two examples are protein lipidation, which often mediates protein localisation to membranes, and redox modification of cysteines. We are interested in developing small molecule probes to mimic or profile these modifications to explore their roles in different biological contexts and with spatio-temporal control.

Structural proteomics. In collaboration with Prof. Frank Sobott we are using chemical tools to understand protein structure and interactions using advanced mass spectrometry approaches.

We are members of the Astbury Centre for Structural Molecular Biology and of Leeds Omics.

Current/recent funding

  • BBSRC – Direct labelling of proteins using Affimer-conjugate warheads for imaging (2018-19), with Darren Tomlinson and Michelle Peckham
  • Leverhulme Trust – Phenotype-directed emergence of unnatural products (2018-22), with Adam Nelson (Leeds) and Terry Smith (St Andrews)
  • MRC DTP studentship – Interkingdom signalling: how Pseudomonas aeruginosa senses and adapts to the host environment  (2018-21), with Daniel Neill and Jo Fothergill (both Liverpool)
  • Royal Society Research Grant – Novel photoaffinity probes to explore ligand binding to formyl peptide receptors (2017-18)
  • Wellcome Trust – Mass spectrometry infrastructure underpinning research into the molecular basis and biological mechanisms in health and disease (2017-21), led by Frank Sobott
  • EPSRC DTP studentship – A chemical approach to unravelling how peptide signals mediate cell-cell communication (2017-21)
  • BBSRC – Structural Insights into Small Molecule Activation of TRPC4/5 Channels (2017-20), with Robin Bon, Stephen Muench, David Beech and Stuart Warriner