ayout 1 - EMBL Grenoble

EMBL Research at a Glance 2009
Thomas
Schneider
PhD 1996, Technical University
of Munich and EMBL.
Postdoctoral research at the
Max-Planck-Institute for
Molecular Physiology,
Dortmund, and the University
of Göttingen.
Group leader at the FIRC
Institute of Molecular
Oncology, Milan.
Group leader at EMBL since
2007. Coordinator of the
EMBL@PETRA3 project.
From a technical
point of view, extracting information from large
amounts of raw structural data (up to hundreds of structures
containing thousands of atoms each) is a very complex
task and requires sophisticated algorithms both for the
analysis and for the presentation and 3D visualisation of the
results. During the last few years, we have been implementing
various algorithms in a framework for the analysis
of different conformations of the same molecule. Presently,
we are expanding the scope of the methods to the investigation
of homologous structures.
Future projects and goals
For the integrated facility for structural biology, our goal is
to provide beamlines that are ready for user experiments by
2010. In small-angle X-ray scattering, the new beamlines
will enable us to work with more complex and more dilute
Tools for structure determination and analysis
Previous and current research
The group pursues two major activities: 1) the construction of three beamlines for structural biology
at the new PETRA III synchrotron in Hamburg; and 2) the development of computational
methods to extract the information from structural data.
The three beamlines we are constructing will harness the extremely brilliant beam of the PETRA
III synchrotron for small angle X-ray scattering on solutions and X-ray crystallography on crystals
of biological macromolecules. The beamlines will be embedded in an integrated facility for
structural biology (www.embl-hamburg.de/services/petra). This facility will support non-specialists
not only in performing the actual experiments with synchrotron radiation but also in sample
preparation and the evaluation of the measured data. The construction of the beamlines is
done in close collaboration with Stefan Fiedler’s team (page 99).
Partly due to the enormous progress in synchrotron radiation-based structural biology, structural
data on biological macromolecules are produced at an ever-increasing rate, creating the need to
develop tools for efficient mining of structural data. We are developing tools for which the central
concept is to use coordinate errors throughout all calculations. The necessity of this approach
becomes clear when one considers that in the contrast to sequence data where a nucleotide entry
can only be right or wrong, the precision in the location of an atom in a crystal structure can vary
over several orders of magnitude; while the position of an atom in a rigid region of a protein giving
diffraction data to high resolution may be known to within 0.01 Å, for an atom in a flexible
region of a poorly diffracting protein, the coordinate error may reach more than 1.0 Å.
Rigid regions (centre; blue and green) identified from ensembles
of structures can be used for superposition and subsequent
analysis (left) or as fragments to interpret experimental data from
methods with lower resolution than X-ray crystallography (right).
samples than presently possible. In macromolecular crystallography, the beamlines will provide features such as micro-focussing and energy
tunability, allowing imaging of the content of small crystals containing large objects such as multi-component complexes.
On the computational side, we will work on improving the error models underlying our methods and on expanding our computational framework
using genetic and graph-based algorithms. We also plan to use recurrent structural fragments extracted from ensembles of structures
as search models in molecular replacement and for the interpretation of low resolution electron density maps. In fact, this aspect of our computational
work will be very helpful in the interpretation of diffraction experiments on weakly diffracting large systems on the future PETRA
III beamlines.
Selected references
Mosca, R. & Schneider, T.R. (2008). RAPIDO: a web server for the
alignment of protein structures in the presence of conformational
changes. Nucleic Acids Res., 36, W2-W6
Schneider, T.R. (2008). Synchrotron radiation: micrometer-sized X-
ray beams as fine tools for macromolecular crystallography. HFSP
Journal, Vol. 2, No. 6, pp. 302–306.
Penengo, L., Mapelli, M., Murachelli, A.G., Confalonieri, S., Magri, L.,
Musacchio, A., Di Fiore, P.P., Polo, S. & Schneider, T.R. (2006).
Crystal structure of the ubiquitin binding domains of rabex-5 reveals
two modes of interaction with ubiquitin. Cell, 12, 1183-1195
Schneider, T.R. (200). Domain identification by iterative analysis of
error-scaled difference distance matrices. Acta Crystallogr. D Biol.
Crystallogr., 60, 2269-2275
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