Recent years have seen intensive activities world-wide in Structural and Functional Genomics based around the exploitation of the ever increasing databases of sequence information from genome sequencing projects. The majority of these programmes concentrate on relatively "low-hanging fruit", in many cases from bacterial sources, in order to pioneer high-throughput technologies (HTPs) for protein overexpression with the resulting proteins destined for structure determination using NMR or protein crystallography. Europe entered this field rather late in the day, after major initiatives had been established in the USA and Japan, with the first EC initiative being the SPINE project (www.spineurope.org), the springboard for the current SPINE2-COMPLEXES proposal. Mainly as a result of these programmes, high-throughput technologies are now available in many laboratories across Europe.
SPINE2-COMPLEXES represents the next logical step along this pathway. It is now timely to attack more challenging biological systems by combining knowledge of the genomes with HTP methods for structural proteomics. SPINE2-COMPLEXES has targeted the development and application of HTP methods for the efficient determination of atomic resolution structures of protein-protein and protein-ligand complexes relevant to human health drawn from the common theme of signalling pathways from receptor to gene. This ambitious programme, focusing on human proteins and their complexes (many of which are transient) will truly challenge the methodologies currently available. The high-throughput technologies will enable the screening of massive numbers of constructs for expression, solubility, stability and the ability to form complexes, rather than reflecting a very large number of proteins targeted for structure determination.
SPINE2-COMPLEXES will further develop and streamline the HTP technologies to address more challenging protein/protein and protein/nucleic acid complexes. Success will demand technological innovation, resulting in new and/or improved HTP procedures at all stages, from cloning, expression and purification, through biophysical and biochemical characterization of individual proteins and complexes, to crystallization, data collection, and solution of structures, as well as solution of smaller protein structures by NMR, and electron microscopy (EM) studies on complexes. As such, the project is far beyond the capacities of individual laboratories working in isolation, which lack both the infrastructure and the critical mass to tackle such a project individually.
The solution of 3D structures of proteins and protein complexes could have a swift impact in terms of providing novel structural information which could, in turn, accelerate the development of novel drugs and biotech products, thus stimulating the relevant European industrial and biotech companies, and enhancing their competitive edge versus their US and Japanese counterparts. Development of new drugs and biotech products would, downstream, benefit health and quality of life within Europe. Therefore, SPINE2-COMPLEXES will have a strategic impact on reinforcing competitiveness of Europe, its biotech and pharma industries and their related SMEs, providing cutting-edge technology as well as valuable information on pharmacological targets (both as individual and complex proteins). In this respect, SPINE2-COMPLEXES will contribute to solving one of the major societal problems of the developed world, i.e. human health in a society with an aging population.
SPINE2-COMPLEXES 031220 is funded by the European Commission FP
