NMR with proteins - from structural biology to structural genomics
Kurt Wüthrich
(Swiss Federal Institute of Technology Zürich, Switzerland)
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 'highthroughput' 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 the four large-scale consortia in the NIHfunded Protein Structure Initiative (PSI), which 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 are due to certain proteins being not readily amenable to crystal structure determination. My research team (the “NMR Core”) works on fi lling 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 structural and other function-related data can be measured under solution conditions close to the physiological milieu in body fl uids.
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 and chemical biology. As illustrations, structural genomics traits of research on prion proteins and on SARS-CoV will be discussed.
