In today’s post-genomic era, with the availability of the complete DNA sequences of a wide range of organisms, structural biologists are faced with new opportunities and challenges in “structural genomics”. In contrast to classical structural biology, research in structural genomics is focused on gene products with unknown structures, unknown functions, and minimal similarity to previously studied proteins. A precisely formulated goal of structural genomics is to determine representative three-dimensional structures for all protein families, which requires ‘high-throughput’ technology for protein production and structure determination, and the long-term outlook is to predict physiological protein functions from knowledge of new three-dimensional structures. The California-based Joint Center for Structural Genomics (JCSG; PI Dr. Ian A. Wilson) is one of four large-scale consortia in the NIH-funded Protein Structure Initiative (PSI). The JCSG developed and operates an extensively automated high-throughput pipeline for protein production, crystallization and crystal structure determination. However, there remain gaps in the coverage of protein fold space that arise because certain proteins are not readily amenable to crystal structure determination. My research team (the “NMR Core”) works on filling such gaps with a ‘high-output’ approach, which involves novel strategies of target selection as well as new technology for NMR structure determination. When compared to structure determination by X-ray crystallography, the NMR method is complementary by the fact that atomic resolution structure determination and measurements of supplementary function-related data can be performed under solution conditions that can be very close to the physiological milieu in body fluids. By generating data on protein structure stability, dynamics and intermolecular interactions in solution, NMR has an exciting role also in the longer-term challenge leading from the expanding protein structure universe to new insights into protein functions, chemical biology and biomedical applications.
The JCSG is supported by the National Institute of General Medical Sciences, Protein Structure Initiative: Grant U54 GM074898.