Kurt Wüthrich is the Cecil H. and Ida M. Green Professor of Structural Biology at The Scripps Research Institute, La Jolla, CA, USA and Professor of Biophysics at the ETH Zürich, Zürich, Switzerland. Kurt Wüthrich studied at the University of Bern, Switzerland, and received his PhD degree from the University of Basel, Switzerland, working with Prof. S. Fallab. He then moved to the US for postdoctoral training with Prof. R.E. Connick, University of California, Berkeley and subsequently to work with Dr. R.G. Shulman at the Bell Telephone Laboratories.
He returned to Switzerland in 1969 to join ETH Zürich, where he became a Professor of Biophysics in 1980. Kurt Wüthrich was the Chairman Biology Department at ETH Zürich 1995-2000. In 2001, he additionally joined the Scripps Research Institute, La Jolla, CA, USA. With more than 700 research articles and reviews, Kurt Wüthrich’s achievements have been recognized by the Prix Louis Jeantet de Médecine, the Kyoto Prize in Advanced Technology, the Nobel Prize in Chemistry, and by a number of other awards and honorary degrees.
His research interests are in molecular structural biology, and in structural genomics. His specialty is nuclear magnetic resonance (NMR) spectroscopy with biological macromolecules, where he contributed the NMR method of three-dimensional
structure determination of proteins and nucleic acids in solution, heteronuclear filter techniques for studies of intermolecular interactions in supramolecular structures, NMR experiments for studies of macromolecular hydration in solution, and the extension of solution NMR studies to very large structures using the principles of transverse relaxation-optimized spectroscopy (TROSY). The Wüthrich group has solved more than 100 NMR structures of proteins and nucleic acids, including the immunosuppression system cyclophilin A–cyclosporin A, the homeodomain–operator DNA transcriptional regulatory system, and the prion protein.
The Wüthrich group started work toward the NMR method for protein structure determination in the mid-seventies with studies on NOE build-up and spin diffusion in proteins, the sequential assignment strategy for proteins and, in joint projects with Richard R. Ernst, the development of two-dimensional NMR with biological macromolecules. A framework for NMR structure determination of proteins was formulated in 1982. Among the three-dimensional protein structures in solution solved by the Wüthrich laboratory, the bull seminal proteinase inhibitor (BUSI) was the first NMR structure of a globular protein. In the further development of the method, the structure determinations of the amylase inhibitor tendamistat, metallothionein, the Antennapedia homeodomain–BS2 operator complex, and the cyclosporin A–cyclophilin A complex were of special interest. Prion proteins (PrP) have become a major research focus of the Wüthrich laboratory since 1994. Beyond three-dimensional structure determination, NMR was used to study biomacromolecular dynamics, solvation and function-related conformational equilibria. The introduction of transverse relaxation-optimized spectroscopy (TROSY) in 1997 has made a wide spectrum of novel NMR experiments available for studies of larger biomacromolecular structures in solution. Applications in the Wüthrich laboratory include structure determinations of integral membrane proteins and studies of their solvation in water-soluble micelles, and characterization of the conformational states of individual macromolecular components in supramolecular structures with molecular weights up to 900 kDa. The Wüthrich laboratory at The Scripps Research Institute has a major focus on NMR applications in structural genomics.
Exploring the Rapidly Expanding Protein Universe
In classical “structural biology”, macromolecular structure determination has been and continues to be primarily focused on molecules of outstanding biological or biomedical interest. In today’s post-genomic era, with the availability of the complete DNA sequences of a wide range of organisms, we have new opportunities in “structural genomics”. Research in structural genomics is focused on gene products with unknown structures, unknown functions, and minimal similarity to previously studied proteins. A precisely formulated initial goal of structural genomics, as formulated in 2000, was to determine representative structures for all protein families, and thus provide a basis for coverage of significant parts of the protein universe with three-dimensional structures. The current program period of the American research program”Protein Structure Initiative (PSI): Biology (http://www.nigms.nih.gov/Research/FeaturedPrograms/PSI/psi_biology/) includes additional function-focused projects.
My research team at The Scripps Research Institute represents solution NMR in three structural genomics consortia, JCSG (http://www.jcsg.org), JCIMPT-Complexes (http://jcimpt.scripps.edu/) and GPCR-Network (http://gpcr.scripps.edu/), which all use structure determination by X-ray crystallography as the principal technique. The presentation will describe our strategies for the use of solution NMR spectroscopy with soluble and membrane proteins in these crystallography-centered environments. We want to ensure an exciting role for NMR in the longer-term challenge leading from increased structural coverage of the continuously expanding protein sequence universe to new insights into protein functions and chemical biology, by generating data on protein structure, conformational equilibria, dynamics and intermolecular interactions in solution.