McCarthy Team

Previous and current research

The team works in close collaboration with the Structural Biology group at the ESRF in the design, construction and operation of macromolecular crystallography (MX) beamlines. We are currently responsible for two MX beamlines, ID14-4 and ID23-2, and the BioSAXS beamline ID14-3. Last year the tuneable beamline ID14-4 was the the first European MX beamline to celebrate a millennium of PDB depositions. It continues to be routinely used by the groups of Venki Ramakrishnan and Ada Yonath, who were awarded the 2009 Nobel prize in chemistry with Thomas Steitz for their ‘studies on the structure and function of the ribosome’. Equally, the microfocus beamline ID23-2 produce smany structures of biologically important molecules, while the highly-automated BioSAXS beamline ID14-3 has already produced several high impact publications in its inaugural year of operation. In January 2010 the team also took over the management of the CRG beamline BM14 at the ESRF, which for the next five years will be run as a partnership with the Indian government and the ESRF, enabling access for Indian and EMBL member state scientists.We also work in close collaboration with the Diffraction Instrumentation Team (page 90) to develop hardware, software and novel methodologies for sample handling and data collection. Recent examples that were funded by SPINE2-Complexes include the prototype BioSAXS liquid handling robot now installed on ID14-3, as well as software for optimal crystal reorientation strategies and the use of X-ray tomography in MX.

The team also studies proteins involved in neuronal development. We are particularly interested in the Slit- Robo signalling complex that is essential for the normal development of the central nervous system and has also been implicated in heart morphogenesis, angiogenesis and tumour metastasis. With part funding by SPINE2 Complexes we have determined a number of structures (see figure) from this system that may be important for the development of novel cancer therapeutics.We are also interested in understanding the molecular mechanismof proteins involved in the biosynthesis of plant secondary metabolites, already publishing the structures of two enzymes involved in caffeine biosynthesis. These studies suggest it may be possible to generate a single protein capable of producing caffeine in plants. Such a possibility, when coupled with caffeine’s ability to act as a natural pesticide, could enable the creation of new ecologically-friendly and pest-resistant plants.

Future projects and goals

On ID14-4 the Synchrotron Crystallography Team will continue to develop novel data collection schemes using the MK3 for challenging structural biology projects and the integration of X-ray tomography methods in MX. On ID23-2 we plan to develop specialised methods for the handling and collection of optimal data from ever smaller crystals. On ID14-3 our team, in collaboration with the Instrumentation Team, the ESRF and EMBL Hamburg, will be actively involved in the provision of a highly automated BioSAXS beamline. On BM14 we will continue to build the new partnership with India and the ESRF for running the beamline in addition to managing a major upgrade of the optical components. We hope that all our combined efforts will push the boundaries of structural biology to better understand the function of more complex biological systems.

In the laboratory we will continue our research on the Slit-Robo complex by trying to decipher how exactly Slit activates Robo on the cell surface.We plan to tackle this by studying larger fragments of Robo and Slit and using complementary methods to MX where necessary. In collaboration with the ESRF MX group and Néstle Research, France, we plan to expand our current research on secondary metabolic pathways in coffee.