Structural Genomics Consortium
Human WDR5 structure in neon as part of a 2006-2007 window display at the Wellcome Trust in London. Credit: Wellcome Library, London
For a protein to work properly it must fold in a specific, precise way. Solving the three-dimensional structure of proteins can be laborious and frustrating, yet this kind of research is vital for understanding how proteins work and for developing drugs to alter their activity. The Structural Genomics Consortium took just over three years to bank 500 protein structures and, with further funding from the Trust and its partners, the international group is continuing to solve medically important proteins at an unprecedented rate.
The Structural Genomics Consortium (SGC) began operations in 2004 with the aim of determining the three-dimensional structure of medically important proteins using a high-throughput approach. The Consortium now operates out of two sites - Oxford, UK, and Toronto, Canada - each of which focuses on proteins of known or potential importance in different disease areas.
The SGC is funded in a distinctive way. Like the SNP (single nucleotide polymorphism) Consortium, which searched for variation in the human genome, the SGC is a not-for-profit organisation funded by public and private funders - currently the Wellcome Trust, nine major pharmaceutical companies, Genome Canada and the Ontario Ministry of Research and Innovation.
All the structures determined by the SGC are made immediately and freely available on the Internet, to allow academics and those working in industry to access the information without delay. Furthermore, the SGC does not place a hold on its structural information until publication - all of the SGC publications are submitted well after the underlying structural information had been made available. The SGC also releases details of the laboratory techniques and protocols developed by its researchers, and hosts open courses on laboratory techniques and a 'visiting scientists' scheme.
From 2004 to 2007, the SGC's target was to solve the structures of 386 medically relevant proteins. In fact, the researchers exceeded this target, solving the structure of over 450 proteins. The SGC banked over 20 per cent of all the new human protein entries added to the Protein Data Bank in 2006 and 2007. By March 2008, the SGC had banked around 600 protein structures from humans and around 100 from human parasites.
As part of the process of structural determination, SGC researchers identified a number of small-molecule inhibitors, which has helped to increase their success rates by stabilising the 'wiggling' of proteins during crystallisation. Not only have these small molecules had practical uses, but some of these inhibitors have potential use in enabling drug discovery.
For example, the Consortium identified 115 potential inhibitors of PIM kinases, a protein family involved in some blood cancers. In collaboration with an oncologist in Basel, one of the inhibitors was shown to have efficacy against cancer cells from acute myeloid leukaemia patients. These results have provided 'pharmaceutical validation' that PIM-1 is an excellent target for therapeutic intervention.
Another focus of the SGC is potential treatments for host diseases. Apicomplexa are a group of parasitic protists that include the malaria parasite Plasmodium. The Toronto group was responsible for 40 per cent of the novel apicomplexan structures banked in the Protein Data Bank in 2005, 67 per cent of those in 2006, and more than 90 per cent in 2007. Together with the Oxford group and the Center for Disease Control (USA), the SGC is exploring the use of bisphosphonate drugs as therapies for cryptosporidiosis.
Work at the Oxford site has focused on a number of key protein families, including the protein kinases, a group of enzymes that contains many valuable drug targets. The SGC's work accounts for half of the world's output of human protein kinase structures to date. Stanley Ng, a graduate student at the SGC in Oxford, published a Nature paper detailing the mechanism by which a particular enzyme affects the chemical modification (methylation) of histones. This type of epigenetic mechanism is thought to be associated with development and disease.
To improve the dissemination of its work, the SGC has created iSee (interactive structurally enhanced experience). This system allows scientists to reach key information on any of the targets solved by the SGC in one place. Each target has an 'iSee datapack', which covers the full range of information generated by the Consortium - including an animated 'guided tour' of each structure, annotations written by experts and other experimental and biological information. iSee datapacks for all structures and the software needed to browse them can be downloaded for free from the iSee website.
In 2007, the Wellcome Trust committed £16 million to a second phase of the Consortium. In this phase, SGC scientists aim to solve the structure of another 670 medically significant proteins. The target list is challenging as it includes a number of human integral membrane proteins. These proteins are notoriously difficult to purify and crystallise because they exist in a fatty environment in the body, while purification must be performed in a water-rich environment.
In December 2008, the Wellcome Trust announced a £4.1 million investment in a new initiative to generate small molecule inhibitors - 'chemical probes' - for 25 proteins involved in epigenetic signalling, and to release these probes into the public domain with no restriction on use. The public-private partnership, to be led by the SGC, also involves GlaxoSmithKline, the National Institutes of Health Chemical Genomics Center in Bethesda, USA, and the Departments of Chemistry and Biochemistry at the University of Oxford.
The initiative aims to develop 'chemical probes', small molecules that can stimulate or block the activity of a protein, specifically designed to affect the activity of proteins involved in epigenetic control. They will complement genetic knockouts and RNAi approaches to understand the role of these proteins in biology. The probes need to be highly selective for their target protein and suitable for use in cellular settings. It is hoped that some probes may be a starting point for drug discovery.
In 2011, the Wellcome Trust provided further funding for the SGC's efforts in structural biology for a further four years. During this phase, the SGC is aiming to solve over 200 structures of soluble proteins and four integral membrane proteins, as well as continuing their programme to develop specific chemical probes for epigenetic signalling proteins. Recent highlights have been the structure of the human zinc metalloprotease ZMPSTE24, which causes laminopathies such as progeria when mutated. The SGC continues to catalyse research in new areas of human biology and drug discovery by focusing explicitly on less well-studied areas of the human genome.
Art and the Structural Genomics Consortium
In 2006, the Graphic Thought Facility design team constructed a colourful and thought-provoking display depicting a number of the Consortium's protein structures in bright neon signs. These were displayed throughout 2007 in the windows of the Wellcome Trust headquarters on Euston Road in London.
For further information, please visit the SGC website.