The search for understanding the mechanisms underlying human diseases and identifying targets for intervention has resulted in a deluge of data from genetic linkage analysis, which is likely to ramp up with current re-sequencing projects. Translating data on disease-linked genes and alleles into mechanistic insights and validated drug targets remains a huge challenge. In particular, many of the genes identified through genetic studies encode proteins with unknown function, or whose role in the disease is unclear.
Our approach is to initiate research on disease-linked genes and mutations by investigating the encoded proteins. The key is to develop and apply a systematic approach whereby both known and “orphan” proteins can be characterized to a satisfactory level. Based on our expertise in protein science, we express and purify relevant domains of the wild-type and mutated proteins, and use these to formulate and test hypotheses about the function of the proteins and the impact of the disease-linked mutations.
Purified proteins can be used to directly for enzymatic activity, binding to small molecules or binding to other proteins. Determination of protein structures by X-ray crystallography can give essential information on their function and evolutionary relationships.
Other Investigations include identification of molecular partners and post-translational modification by mass spectrometry, screening for small-molecule ligands, and generation of specific antibodies. The reagents and information can be used in partnership with scientists involved in the clinical investigation of the relevant diseases to further our understanding of the changes occurring in patients and to evaluate the therapeutic implications.
As part of the structural genomics effort, we continue to determine structures and characterize the biochemistry of medically-relevant human proteins. The group has focussed on DNA helicases and nucleases involved in DNA repair (pictured). DNA repair mechanisms are emerging as an potential new target for cancer therapy. Cancer cells are defective in DNA repair and are genetically unstable; it is thought that further inhibition of the remaining repair pathways will selectively kill cancer cells with little effect on other cells in the body. To explore this possibility, we have been screening and developing small-molecule inhibitors of the DNA helicases RECQ1 and BLM, which are currently evaluated for their impact on cultured cancer cells.