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Mass Spectrometry based Structural Biology.

Native mass spectrometry is an expanding approach for studying intact biomolecular assemblies in the gas-phase, whilst retaining their solution structural fold and architecture.  This process allows us to investigate the assembly, stoichiometry, topology and stability of biomolecular assemblies and is fast becoming an important technique in structural biology.

In our research group,  a range of native mass spectrometry and ion mobility techniques are brought to bear on a range of in-house and collaborative projects

Top-Down Protein Fragmentation.

We have a long standing interest in the application of top-down protein mass spectrometry. This technique makes use a range of dissociation techniques to fragment intact protein ions, and has traditionally been a powerful technique for investigating protein post-translational modifactions (PTMs). We are now using these techniques to perform top-down analyses of native proteins, protein-ligand and protein-protein complexes. 


In addition, we are investigating the possibility of increasing the efficiency of top-down fragmentation techniques by controlling the chemistry of sample solutions and manipulation of the ionisation conditions. 

A Multimodal Mass Spectrometry Platform for the Analysis of Protein Redox Modifications.

The intracellular redox environment is a highly compartmentalised and regulated state function which varies considerably in differing subcellular location and during cell cycle, cell differentiation and cell death. Disregulation of cellular redox potential, particularly to pro-oxidative states, is implicated in the initiation and proliferation of several disease states (e.g. cardiovascular disease, neurodegenerative disease and cancer).

Flux in cellular redox potential can directly influence protein structure by altering the oxidation state of redox-sensitive cysteine (Cys) residues.There is an emerging realisation that these reversible redox modifications (RMs) are used in many proteins as molecular switches to regulate their function or activity. Therefore, investigating the molecular details and the structural/functional consequences of RMs in susceptible proteins is crucial in understanding their biochemical regulation. Similarly, influencing a protein’s function by targeted chemical modification of specific Cys residues has been proposed as a potential strategy to manipulation cellular pathways in disease treatment.

We are developing a multimodal platform of modern MS-based techniques to

           (i) comprehensively describe the chemistry of specific Cys RMs;

           (ii) accurately quantify their redox-midpoint potentials;

           (iii) determine the structural consequences resulting from specific RMs; and ultimately,

           (iv) link our structural findings to protein function.

We have recently used this platform technology to delineate potential redox regulation mechanisms in the tumour supressor p53. 

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