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Solution structure by NMR spectroscopy

David Neuhaus

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Medical Research Council (MRC)
We will use NMR spectroscopy, and where appropriate X-ray crystallography, to determine the structures of a number of proteins and their complexes with DNA, with peptides and with other proteins. Where possible, high-resolution structures of the relevant complexes will be determined directly using extensive NOE measurements; in the cases of some weaker complexes (e.g. those of proteins with small peptides derived from the sequence of a larger binding partner), ligand footprinting will be carried out using a combination of chemical shift titrations, cross-saturation experiments and, where possible, intermolecular NOE measurements. A key component of the work will be a study of human poly-ADPribose polymerase-1 (PARP-1); this protein detects and signals the presence of DNA single-strand breaks so as to initiate repair, and it is an important target in cancer therapy. NMR is particularly well-suited to characterise the intermolecular and interdomain interactions that underpin PARP-1’s molecular mechanism of action upon DNA recognition. Other targets for study will be selected from amongst the projects ongoing in other groups at LMB and CIMR, and will be undertaken as collaborations. In particular, protein structures and protein-peptide interactions relevant to vesicle trafficking and intracellular immunity will be studied, among others. Solution structures of a number of protein domains and their complexes will be determined.

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