Structural Proteomics In Europe (SPINE) is an integrated research project which brings together some of the top European structural biology institutions in an unprecedented collaborative effort to develop new methods and technologies for high-throughput structural biology.
It is aimed at determining structures of proteins and protein complexes directly relevant to human health and diseases.
SPINE is funded within Framework V of the European Commission for three years from 1 October 2002 and co-ordinated by Professor Dave Stuart, Division of Structural Biology, University of Oxford.
BIOXHIT is a unique project in the field of structural genomics funded by the European Commission for 4 years (from January 2004 to December 2007) with a total budget sum of about 10 million Euros.
The ability of post-genomic research in biology and medicine to deliver substantial improvements in human health depends critically on the rate of progress towards the understanding of complex biological processes at the molecular level, which in return depends on your capability of rapidly determining the 3D structures of all molecules involved in atomic detail. Biological crystallography aims to create precise, three-dimensional "architectural" models of biological molecules. Without such models at hand, it is close to impossible to understand biological processes, for instance the way proteins and other molecules behave in cells, or to design new drugs that will affect their functions.
BIOXHIT is mobilising on the one hand all European synchrotron facilities with beamlines equipped for macromolecular crystallography, either already in existence or planned for the future, and on the other hand most of the software developers active in fields relevant to high-throughput structure determination. This represents the greatest possible mobilisation of resources at the European level, both in terms of infrastructure and scientific talents.
This project aims to perform a ground-breaking impact on the identification of potential new drug targets against RNA viruses through comprehensive structural characterization of the replicative machinery of a carefully selected and diverse set of viruses. RNA viruses include more than 350 different major human pathogens and most of the etiological agents of emerging diseases: viruses of gastroenteritis (>1 million deaths annually), measles (>45 million cases and >1 million deaths annually), influenza (>100 million cases annually), dengue fever ( 300 million cases annually), enteroviruses and encephalitis (several million cases of meningitis annually), hepatitis C virus (>150 million infected persons in the world). The SARS outbreak has dramatically demonstrated how high could be the economic cost of an epidemic caused by an emerging virus. This negative impact is actually widening every day, as many governments are forced to make costly arrangements to cope with the threat of bio-terrorism, which lists some deadly RNA viruses in its arsenal. To meet these challenges science needs to look for new therapeutic and prophylactic substances active against RNA viruses since those currently available are scarce and of poor potency. The common strategies used for the development of antiviral drugs are mainly based on the knowledge accumulated through studies of virus genetics and structure. Yet, it is a strange paradox that genomic and structural characterisation of RNA viruses was not accepted as a priority until very recently.
3D-REPERTOIRE
Progress of modern day biology will require understanding and harnessing the network of interactions between genes, proteins and the functional systems that these produce. Given the complexity of even the most primitive living organism, and our still very limited knowledge, it is unreasonable to expect that we might, in the near or even medium term, reach such understanding at the level of an entire cell. A prequesite for this goal is an understanding of the biological function of the complete set of genes and proteins within genomes (post-genomic biology). Proteins rarely act alone: they typically interact with other macromolecules to perform particular cellular tasks. The resulting functional assemblies (complexes) are more than the sum of their parts. They have a function that is not easily understood by even the most systematic analyses of single proteins. Thus the discovery and analysis of particular cellular protein complexes under physiological conditions provides key insights into their function, and takes the characterisation of the system well beyond the limits of other experiments. Prominent examples include the ribosome, the chaperonin GroEl/GroEs, the spliceosome, the cyclosome, the proteasome, the nuclear pore complex and the synaptosome. Analyses of results from genome-scale interaction discoveries in yeast show a clear tendency for many yeast assemblies to mirror their equivalents in animals, including the model organisms and man. Complexes essential for the cell overlap significantly, and represent the building blocks of a Eukaryotic core proteome covering basic cellular function. More importantly, those conserved between yeast and man will contribute significantly to the understanding of multifactorial diseases, particularly those related to key cellular processes. Elucidation of three-dimensional (3D structures for protein complexes will open new avenues to unravel the molecular pathology and physiology of human diseases, leading to rational, target-oriented therapeutic approaches. Moreover developments in 3D tomography show that it will soon be possible to fit such structures into a whole cell tomogram. . This will be a great leap for Systems Biology, since it will place complexes in their precise cellular context, and provide critical concentration information essential for the quantitative understanding of a living cell. However, without the individual complexes, it will be exceedingly difficult to understand such whole cell images. 3D-Repertoire aims to obtain structures for all amenable protein complexes from budding yeast (or where necessary equivalents from other species) at the best possible resolution by Electron Microscopy, X-ray Crystallography and In Silico approximations. For this purpose we have created a team of top scientists covering all the expertise needed for such an ambitious undertaking and we have in our consortium the company Cellzome. This company has done the complete pull-down study of complexes in Yeast. In this way we will have access to all the relevant information as well as clones, necessary to carry on an ambitious project like this one.