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The Centre brings together a large group of structural molecular biologists, chemists and physicists working on the structure and function of a wide range of biological molecules, biomolecular assemblies and complexes. It specialises in all the current major techniques for high-resolution structure determination of large molecules, including X-ray crystallography, NMR spectroscopy, and electron microscopy as well as a battery of sophisticated biophysical tools such as mass spectrometry, surface plasmon resonance and time-resolved spectroscopies. These techniques are complemented by theoretical approaches such as molecular modelling and bioinformatics. Structural studies, however, are not taken in isolation, and the mission of the Centre is to integrate these with powerful programmes of functional analysis, since the ultimate goal of biology is to understand the function of biological systems rather than just their structure. The enormous success and potential of genome projects is generating a flood of information on protein sequences and the challenge for the Centre over the coming years is to assign structure and function to the products of the genes that have been sequenced.

The current research priorities of the Centre are divided into five major themes:

Protein-DNA/RNA Interactions underpin the fundamental processes by which the genetic information in DNA and RNA is controlled. Studies of protein-DNA complexes include intermediates in genetic recombination where resolvases bind to four-way DNA Holliday junctions to cleave them back to duplexes, DNA polymerases (especially as potential drug targets), transcriptional repressors and activators, restriction endonucleases, helicases, repair enzymes and plasmid replication initiator proteins. Studies on protein-RNA complexes exploit particular expertise in RNA synthesis technology, and include novel approaches such as a phage capsid supramolecular support system for RNA structure determination by crystallography in the absence of RNA crystals. Major interests also centre around RNA structures in pathogenic RNA viruses that may allow new routes to therapies in the future.

Membrane Proteins constitute a huge class of critically important molecules, especially in higher organisms. Their genes occupy as much as a third of the genome, and they also constitute the majority of known drug targets. The Centre has a major programme of structural and functional studies on several classes of membrane proteins, including membrane transporters and ion channels. Prokaryotic and eukaryotic membrane transporters, that translocate sugars, nucleotides, antibiotics or other solutes across membranes form a particular focus. The Centre is also a key component of the "Membrane Protein Structure Initiative" (Mpsi), a major BBSRC-funded UK consortium applying high-throughput, automated structural genomics methods to determine crystal structures of membrane proteins.

Protein Folding and Assembly have assumed particular importance with the relatively recent recognition that a number of serious diseases (such as CJD, BSE, Alzheimer's and haemodialysis-related amyloidosis) result from folding disorders. There is a vigorous programme studying the molecular mechanisms of protein folding, both for proteins with simple folds, such as helical bundles and beta meanders, and more complex topologies such as Greek key domains, together with a project on the molecular chaperone GroEL. The structures of intermediates in the folding pathways are investigated using NMR, stopped-flow fluorescence and circular dichroism (CD), protein engineering and hydrogen-exchange using electrospray mass spectrometry (ESMS). Highlights include the dissection of the folding pathway for pseuodoazurin and CD2, as well as detection of different folding mechanisms for bacterial immunity proteins. Recent innovations are the construction of temperature-jump apparatus capable of monitoring folding transitions in nanoseconds and of a mechanical device for unfolding single protein molecules (see Methods Development). Direct studies of folding of proteins responsible for folding diseases such haemodialysis-related amyloidosis and Alzheimer's are also underway.

Molecular Recognition and Catalysis covers a wide range of studies of enzyme mechanism and specific recognition between molecules. Several medically important enzymes are being studied structurally as potential drug targets, such as angiotensin-converting enzyme and other membrane-bound peptidases, bacterial cell wall synthesising enzymes and the human clotting factor XIII. A comprehensive programme on the structure and mechanism of copper-containing galactose and amine oxidases is aimed at elucidating the chemistry of the catalytic pathway in atomic detail, by determining the structures of all the reaction intermediates using novel anaerobic and cryogenic trapping techniques. A programme of enzyme design is aimed at engineering aldolases to produce novel enzyme catalysts for stereospecific carbon-carbon bond formation. Recognition studies mainly centre around protein-carbohydrate complexes that are critically important for infectious diseases where micro-organisms use them as a route for initial infection or as targets for toxins.

Methods Development in the centre covers a number of areas. Protein single molecule mechanics is a major new area and covers both studies on muscle mechanism and protein unfolding. Methods are available to unfold single protein molecules while measuring both he necessary force and the associated spectroscopic changes. Major advances in single-particle EM image processing are being made in many laboratories and the Centre has a programme to extend this to transient molecular conformations and complexes by a spray-mixing method allowing millisecond time resolution. Developments in NMR include new methods for analysing oligosaccharide complexes and protein folding intermediates. Bioinformatics programmes are aimed at automatic ligand design to generate new pharmaceuticals and new methods for analysing genome sequence information in terms of the predicted structure and function of the encoded proteins.

These projects and more are described in detail in the research pages of individual Centre members.

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