The National Institute of General Medical Sciences (NIGMS****For further information on NIGMS funding: http://www.nih.gov/nigms/funding/psi.html; Bethesda, MD, USA), one of the US National Institutes of Health, is set to spend up to US $18 million each year for up to five years on the emerging field of structural genomics. The funding is part of the institute’s Protein Structure Initiative (PSI) and will be awarded to up to six US research centres.Unlike functional genomics, which investigates the cellular and phenotypic functions of genes, structural genomics investigates gene function in terms of the consequences of molecular shape. The aim is to solve the three-dimensional structure of every protein encoded by the human genome, using X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. Protein structure determination is renowned for being slow and empirical. ‘Fortunately, with recent technological advances and new public funding we now have the opportunity to scale up these techniques and increase the throughput of this process’, says Chris Sander, Chief Information Science Officer, Millennium Predictive Medicine and Visiting Professor, Massachusetts Institute of Technology (Cambridge, MA, USA). The use of synchroton radiation in crystallography, cryocrystallography, selenomethionine for phasing, more powerful NMR machines and other advances, together with improved computational techniques that facilitate automation, make the goal of characterizing all 100 000 human proteins a real possibility.‘We can also increase the efficiency of the process by targeting families of proteins rather than individual proteins and by preventing duplication of effort,’ Sander explains. ‘We can group proteins into families with similar sequence patterns and somewhat related function and then pick one or more from each family to characterize. Initial targets will be proteins encoded by genes of, for example, medical or evolutionary interest,’ he says. Once the structure of a protein is known, techniques such as model building by homology and molecular replacement enable the three-dimensional shape of other members of its family to be elucidated. Relationships between the shapes of protein folds help narrow down the function of each molecule and provide information to build new computational tools to predict the function of other proteins.The location of binding sites and the determination of specificity, catalytic activity, and regulatory mechanisms that involve conformational changes and covalent modifications are likely to be of particular interest in the design of new drugs. Moreover, ‘if we can interpret genetic variations between individuals and map those changes in protein shapes, we can do a better job in targeting drugs at specific patient populations or redesigning drugs to reduce the side-effects that affect certain groups of people,’ says Sander.A PSI website (http://www.structuralgenomics.org/) has been created to encourage scientists working in this field to share their results and prevent them duplicating their efforts. ‘In addition to that we are also trying to organize discussions between key experimenters in the USA, Europe, and Japan to get implicit support for a systematic approach to this problem. We also hope to announce a structural genomics project that will follow in the footsteps of the Human Genome Project and encourage open exchange of information,’ says Sander. ‘Given the right level of public funding, a very rough estimate of the time scale for such a project would be 10 000 proteins in the next five years,’ concludes Sander.
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