... understanding life in molecular detail

Dr Megan Wright

chemical biology, proteomics, chemical probe, protein labelling


Our interests are in developing creative chemical tools to understand biology and tackle important questions in health and disease. We synthesise probes to detect and manipulate small molecule-protein interactions and modifications in live cells, with a focus on host-pathogen interactions. This research is highly interdisciplinary and spans organic and peptide synthesis, bioorthogonal ligation chemistry, protein biochemistry, cell biology and quantitative mass spectrometry-based proteomics.

Current major projects include:
  • Unravelling host-microbe communication with photoprobes
  • Chemical proteomics to map GPCR-ligand binding sites
  • Profiling cellular pathways with (re)activity-based probes

The response of cells or organisms to small molecule signals and drugs is of fundamental importance for biology and drug discovery, and is often mediated by interactions with proteins. We aim to apply chemical tools to understand such interactions at the molecular level, but in live cells or tissues.

We are particularly interested in exploring native small molecule-protein interactions in complex biological systems. For example, there is increasing evidence that bacterial and human cells ‘listen in’ 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. One area of our work is in ‘weaponising’ compounds with photo- or chemically-reactive functionalities to stabilise their interactions with protein targets. Probes are typically also equipped 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.

As well as interacting non-covalently with small molecules, proteins are widely modified by them, both enzymatically and spontaneously, exerting exquisite and rapid temporal control over protein function. An example is protein lipidation, which often mediates protein localisation to membranes. We are interested in developing small molecule probes to mimic or profile these modifications to explore their roles in different biological contexts.

We apply a wide variety of biological methods to support, validate and characterise the findings from chemical proteomics experiments. For example, we use global proteomic analysis to profile changes in the cellular proteome in response to different stimuli, such as a chemical probe, and thereby shed light on small molecule mode of action.

A fully-funded PhD studentship, joint with Prof Frank Sobott and Prof Richard Bayliss in the Astbury Centre, is available for start October 2017. Details are given here:

https://www.findaphd.com/search/ProjectDetails.aspx?PJID=83873 

Detailed research programme                  Close ▲
MHW.jpg

University Academic Fellow (Leeds) 2016-present

MRSC

PhD student (Imperial College London), 2009-2013
EPSRC Doctoral Prize Fellow (Imperial College London) 2013-2014
Marie Sk?odowska-Curie Fellow (University of Munich) 2014-2016

G18.b
School of Chemistry
0113 34 33196
m.h.wright@leeds.ac.uk
http://www.chem.leeds.ac.uk/People/Wright.html

Selected Publications

  1. Wright MH, Paape D, Price HP, Smith DF, Tate EW Global Profiling and Inhibition of Protein Lipidation in Vector and Host Stages of the Sleeping Sickness Parasite Trypanosoma brucei. ACS infectious diseases 2 427-441, 2016

  2. Wright MH, Sieber SA Chemical proteomics approaches for identifying the cellular targets of natural products. Natural product reports 33 681-708, 2016

  3. Wright MH, Paape D, Storck EM, Serwa RA, Smith DF, Tate EW Global analysis of protein N-myristoylation and exploration of N-myristoyltransferase as a drug target in the neglected human pathogen leishmania donovani Chemistry and Biology 22 342-354, 2015

  4. Wright MH, Clough B, Rackham MD, Rangachari K, Brannigan JA, Grainger M, Moss DK, Bottrill AR, Heal WP, Broncel M, Serwa RA, Brady D, Mann DJ, Leatherbarrow RJ, Tewari R, Wilkinson AJ, Holder AA, Tate EW Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach Nature Chemistry 6 112-121, 2014