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The Wüthrich Laboratory

Kurt Wüthrich: Research Highlights/Selected Publications

Kurt Wüthrich's research interests are in molecular structural biology and in structural genomics. His specialty is nuclear magnetic resonance (NMR) spectroscopy with biological macromolecules, where his research group contributed the NMR method for 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 (1) and, in joint projects with Richard R. Ernst, the development of two-dimensional NMR with biological macromolecules (2). A framework for NMR structure determination of proteins was formulated in 1982 (3).  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 (4).  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 (5–8). The introduction of transverse relaxation-optimized spectroscopy (TROSY) in 1997 (9) 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 (10), and characterization of the conformational states of individual macromolecular components in supramolecular structures with molecular weights up to 900 kDa (11).  The Wüthrich laboratory at The Scripps Research Institute has a major focus on NMR applications in structural genomics (12). 

Kurt Wüthrich: References to “Research Highlights”

1. Dubs, A., Wagner, G. and Wüthrich, K. (1979) Biochim. Biophys. Acta 577, 177–194. Individual assignments of amide proton resonances in the proton NMR spectrum of the basic pancreatic trypsin inhibitor.

2. Wüthrich, K., Wider, G., Wagner, G. and Braun, W. (1982) J. Mol. Biol. 155, 311–319. Sequential resonance assignments as a basis for determination of spatial protein structures by high resolution proton nuclear magnetic resonance.

3. Anil-Kumar, Ernst, R.R. and Wüthrich, K. (1980) Biochem. Biophys. Res. Comm. 95, 1–6. A two-dimensional nuclear Overhauser enhancement (2D NOE) experiment for the eclucidation of complete proton–proteon cross-relaxation networks in biological macromolecules.

4. Williamson, M.P., Havel, T.F. and Wüthrich, K. (1985) J. Mol. Biol. 182, 295–315. Solution conformation of proteinase inhibitor IIA from bull seminal plasma by 1H nuclear magnetic resonance and distance geometry.

5. Lopez Garcia, F., Zahn, R., Riek, R. and Wüthrich, K. (2000) Proc. Natl. Acad. Sci. USA 97, 8334–8399. NMR structure of the bovine prion protein.

6. Wüthrich, K. and Wagner, G. (1975) FEBS Lett. 50, 265–268.
NMR investigations of the dynamics of the aromatic amino acid residues in the basic pancreatic trypsin inhibitor.

7. Otting, G., Liepinsh, E. and Wüthrich, K. (1991) Science 254, 974–980. Protein hydration in aqueous solution.

8. Billeter, M., Güntert, P., Luginbühl, P. and Wüthrich, K. (1996) Cell 85, 1057–1065. Hydration and DNA recognition by homeodomains.

9. Pervushin, K., Riek, R., Wider, G. and Wüthrich, K. (1997) Proc. Natl. Acad. Sci. 94, 12366–12371. Attenuated T 2 relaxation by mutual cancellation of dipole–dipole coupling and chemical shift anisotropy indicates an avenue to NMR structures of very large biological macromolecules in solution.

10. Fernández, C., Hilty, C., Wider, G. and Wüthrich, K. (2002) Proc. Natl. Acad. Sci. USA 99, 13533–13537. Lipid–protein interactions in DHPC micelles containing the integral membrane protein OmpX investigated by NMR spectroscopy.

11. Fiaux, J., Bertelsen, E., Horwich, A. and Wüthrich, K. (2002) Nature 418, 207–211. NMR analysis of a 900K GroEL–GroES complex.

12. Page, R., Peti, W., Wilson, I.A., Stevens, R.C. and Wüthrich, K. (2005) Proc. Natl. Acad. Sci. USA 102, 1901–1905. NMR screening and crystal quality of bacterially expressed prokaryotic and eukaryotic proteins in a structural genomics pipeline.