Generation of Protein Structures for the 21st Century

Abstract

I am personally not excited about solving structures with novel folds so I am not a participant in a PSI-2 production center. My interests are in structural neurobiology and in developing critically needed technologies that help myself and others accomplish their research goals. However, I do appreciate the passion the PSI-2 production centers have for their work and understand and appreciate the big picture that will result from their dedicated effort, as I also appreciate the enormous efforts of those working on viruses, ribosomes, and other very challenging structural biology projects. Once PSI-2 is completed in the summer of 2010, the issue of how we will generate the structural data that the scientific community needs will not go away. Protein structures will continue to be critical for the understanding of chemistry and biology. Key considerations for a Protein Initiative-3 (or 1) include:•Careful re-evaluation of the targets/approaches for biomedical research.•Continuation of technology development. This is critical for studying the larger complexes and challenging proteins like those that exist in the membrane. We also need increased production of these very challenging protein structures so that we improve our fundamental understanding of these key biological macromolecules.•Function is as important as the structures being generated and this should become a more central focus of any future program. Already, movement is evident in this area with chemical profiling of protein families in a structural genomics setting (Allali-Hassani et al., 2007xStructural and chemical profiling of the human cytosolic sulfotransferases. Allali-Hassani, A., Pan, P.W., Dombrovski, L., Najmanovich, R., Tempel, W., Dong, A., Loppnau, P., Martin, F., Thornton, J., Edwards, A.M. et al. PLoS Biol. 2007; 5: e97CrossRef | PubMed | Scopus (32)See all ReferencesAllali-Hassani et al., 2007).•Better coordination with other proteomics approaches (e.g., activity-based profiling, metabolite profiling of enzyme families, and mass spectrometry differentiation among various cellular species).•Although we have seen X-ray and NMR complement one another better through PSI, electron microscopy has not been integrated as well, in part due to the proteins being studied. As we start to investigate larger complexes, the membrane, and entire cells, electron microscopy and single molecule analysis advances will be extremely important techniques to integrate and further our understanding of biological structures and their functions.There is no question that certain things could be done better in PSI, as is often the case when change occurs. What is important is that we have made tremendous strides in improving our approaches to collect and understand protein structures in the past several years, and we are now in a better position to keep up with the demand for more structural data. I applaud NIGMS staff for talking to scientific leaders about current limitations and potential new directions in the field, and for taking the initiative to change the way we do science based on prior investments and new discoveries.