ayout 1 - EMBL Grenoble

EMBL Grenoble
Synchrotron Crystallography Team
Previous and current research
The Synchrotron Crystallography Team, in close collaboration with the MX group of the European
Synchrotron Radiation Facility (ESRF), is involved in the design, construction and operation of
macromolecular crystallography (MX) beamlines. We are currently responsible for two macromolecular
beamlines (ID14-4 and ID23-2) and the newly constructed BioSAXS beamline at ID14-
3. The MAD beamline ID14-4 was the first undulator MX beamline to celebrate a decade of user
service and has been instrumental in the structural determination of biologically important molecules
as well as significantly contributing to pioneering radiation damage studies on biological
samples. The highly successful microfocus beamline ID23-2 was the first such beamline in the
world, and the newly converted BioSAXS beamline ID14-3 commenced user operation in November
2008. The team also provides scientific and technical support for the CRG beamline BM14
at the ESRF. This partnership with the UK MRC and India enables access to BM14 for 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 possibilities. Recent examples (funded by BIOXHIT) include the mini-kappa goniometer
head (MK3) and associated software for optimal crystal reorientation strategies as well
as the use of X-ray tomography in MX (figure 1).
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. This signalling system has also been implicated in heart morphogenesis, angiogenesis
and tumour metastasis. With part funding by SPINE and SPINE2Complexes we have determined
a number of structures (figure 2) from this system that maybe important for the development of novel cancer therapeutics. We are
also interested in understanding the molecular mechanism of proteins involved in the biosynthesis of plant secondary metabolites, and recently
published 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 new ecologically friendly and pest-resistant plants to be created.
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 collecting of optimal data from ever smaller crystals. On ID14-3 our team, in collaboration with the Instrumentation team,
the ESRF, and the EMBL Hamburg, will be actively involved in the provision of a highly automated BioSAXS beamline. On BM14 we will form
a new partnership with India and the ESRF for running the beamline. We hope that all our combined efforts will push the boundaries of protein
crystallography currently available to better understand the biological functions 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.
Andrew
McCarthy
PhD 1997, National University
of Ireland, Galway.
Research associate, Utrecht
University.
Postdoctoral research at
Massey University and
Auckland University.
Staff scientist at EMBL
Grenoble.
Team leader at EMBL
Grenoble since 2007.
Figure 1: Cover illustration for the 2009 J. Appl. Cryst.;
see Brockhauser et al.
Figure 2: Structure of Slit2 D2 bound to Robo1 Ig1.
Selected references
Brockhauser, S., Di Michiel, M. McGeehan, J.E., McCarthy, A.A. &
Ravelli, R.B.G. (2008). X-ray tomographic reconstruction of
macromolecular samples. J. Appl. Cryst., 1, 1057-1066
Martinez Molina, D., Wetterholm, A., Kohl, A., McCarthy, A.A.,
Niegowski, D. et al. (2007). Structural basis for synthesis of
inflammatory mediators by human leukotriene C synthase. Nature,
8, 613-616
McCarthy, A.A. & McCarthy, J.G. (2007). The structure of two N-
methyltransferases from the caffeine biosynthetic pathway. Plant
Physiol., 1, 879-889
Morlot, C., Thielens, N.M., Ravelli, R.B., Hemrika, W., Romijn, R.A.,
Gros, P., Cusack, S. & McCarthy, A.A. (2007). Structural insights into
the Slit-Robo complex. Proc. Natl Acad. Sci. USA, 10, 1923-1928
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