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My laboratory is concerned with the use of X-ray crystallography to determine structure/function relationships in proteins. Such studies provide a powerful route towards understanding basic biological mechanisms, contribute towards the rational design of new drugs and underpin the use of enzymes for industrial and biomedical applications.

A major programme in the laboratory concerns progress towards the design of novel herbicides and a recent highlight includes the structure determination of A. thaliana imidazoleglycerol-phosphate dehydratase, an enzyme of histidine biosynthesis and a target for the experimental family of triazole phosphonate herbicides.

The structure is composed of twenty-four identical subunits arranged in 432 symmetry and shows how the formation of a novel dimanganese cluster is crucial to the assembly of the active 24mer from an inactive trimeric precursor and to the formation of the active site of the enzyme.

Molecular modelling suggests that the substrate is bound to the manganese cluster as an imidazolate moiety (Fig 1b) which subsequently collapses to yield a diazafulvene intermediate.

The mode of imidazolate recognition exploits pseudo-symmetry at the active site arising from a combination of the assembly of the particle and pseudo-symmetry present in each subunit as a result of gene duplication.

This provides an intriguing example of the role of evolution in the design of Nature’s catalysts and has opened up the opportunity of analysing the mode of inhibitor binding as a contribution towards a programme of rational herbicide design.