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Protein modification and engineering

Protein engineering and synthetic biology

The rational engineering of proteins to generate defined functional materials is a major interest in the group. We have interests in both the application of known methodology, such as the use of bioorthogonal cross-linking chemistry and Amber suppression and the development of new methods such as the application of sortases (see below). A major current interest is the modification of the bacterial toxoids, such as that from cholera. Many members of the group are working with Mike and his close collaborator Dr Bruce Turnbull to chemically and genetically modify this class of proteins for potential application in drug delivery, the generation of protein-derived materials and sensing of unnatural glycosides. This work is currently supported by funding from both BBSRC and GSK.

We are also working with Prof. Andy Wilson to engineer the aromatic oligoamides (which he has generated as analogues of α-helices) into intact proteins to thereby generate 'bionic proteins'.

Protein modification using Sortase

Optimised strategy for N-terminal protein modification reported in Williamson et al (Angew. Chemie, 2012)

We are interested in the application of all kinds of protein modifications but have particular interests in the application of Sortases as generic tools for protein modification. We have recently reported an optimised protocol for N-terminal labelling of proteins using depsipeptide substrates. This provides a convenient, quantitative route to generate labelled proteins, superior to the use of less-selective reagents such as activated esters and readily applicable to other systems.

We are now using this approach in a variety of model systems as well as seeking to develop further chemoenzymatic modification strategies.

Publications in this area

Chemical generation and modification of peptides containing multiple dehydroalanines
Phillip M. Morrison, Patrick J. Foley, Stuart L. Warriner & Michael E. Webb Chem. Commun. (2015) 51 13470-3

Depsipeptide substrates for sortase-mediated N-terminal protein ligation
D. J. Williamson, M. E. Webb & W. B. Turnbull Nat. Protoc. (2014) 9 253-262

Efficient N-terminal labelling of proteins by use of Sortase
Daniel J. Williamson, Martin A. Fascione, Michael E Webb and W. Bruce Turnbull Angew. Chem. (2012) 51 9377-9380

Oligobenzamide proteomimetic inhibitors of the p53-hDM2 protein-protein interaction.
Jeffrey P Plante, Thomas Burnley, Barbora Malkova, Michael E Webb, Stuart L Warriner, Thomas A Edwards and Andrew J Wilson Chem. Commun. (2009) 5091