Structural and Chemical biology of protein phosphatases and signalling proteins

Reversible phosphorylation of proteins is the main regulatory mechanism in signal transduction pathways. Triggered by external stimuli, the balance between the activities of protein kinases and protein phosphatases controls diverse cellular processes, like cell proliferation and differentiation, neoplasic transformation, cell adhesion and metabolism. Alteration in the expression profiles, catalytic activities and 3-dimensional structures of protein kinases and phosphatases are responsible for a large number of decimating diseases (diabetes, cancer, neuropathies), which are still difficult to treat.

The main focus of our research is to elucidate the molecular basis for macromolecular recognition and specificity in signalling events. Using X-ray crystallography and other biophysical and biochemical methods, we study the interaction of signalling protein (phosphatases, kinases) with their biological targets and ligands. 

Signalling pathways, and in particular phosphatases, are key players  in many human diseases and essential virulence factors in pathogenesis. An important part of our research is now focused on the chemical intervention of such targets through different programmes of drug discovery and structure-based drug design. In vitro screening and computational design are combined with cell validation of inhibitors and then translated to relevant animal models in collaboration with laboratories across Europe and US.

Chemical intervention of human diseases is still a considerable challenge despite the efforts of many pharmaceutical research efforts. In recent years, the significant improvement in both computational and robotics power has allowed the development of high-throughput screening programmes to identify new drug candidates. However, the best outcomes are often the result of specialised knowledge in particular biological processes and systems that steams from academic laboratories in the first instance. Our long standing expertise on protein phosphatases has given us the opportunity to exploit this knowledge and to engage in a number of very exciting drug-discovery programmes. We select protein targets that play critical roles in either cancer development or infectious diseases and combine experimental and computational screening with structure-based drug design to produce new drug candidates for preclinical trials.