Kurt Wüthrich's research interests are in molecular structural biology, protein science and structural genomics. His specialty is high resolution nuclear magnetic resonance (NMR) spectroscopy with biological macromolecules. Wüthrich's contributions to techniques development include 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 molecular weights with the use of transverse relaxation-optimized spectroscopy (TROSY) and cross-correlated relaxation-enhanced polarization transfer (CRINEPT). The Wüthrich group has solved more than 50 NMR structures of proteins and nucleic acids, including the immunosuppression system cyclophilin A–cyclosporin A, the homeodomain–operator DNA transcriptional regulation system, and the murine, human and bovine prion proteins. Wüthrich's bibliography includes over 600 papers and reviews, and three monographs: NMR in Biological Research: Peptides and Proteins, North-Holland, Amsterdam, 1976; NMR of Proteins and Nucleic Acids, Wiley, New York, 1986; NMR in Structural Biology, World Scientific, Singapore, 1995.

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 introduction of the still widely used sinebell digital filter, the sequential assignment strategy for proteins (1) and, in joint projects with R.R. Ernst, the development of two-dimensional NMR with biological macromolecules. A framework for NMR structure determination of proteins was formulated in 1982 (2), which has so far proven sufficiently general to accommodate subsequent technical advances. Among the three-dimensional protein structures in solution solved by the Wüthrich laboratory, bull seminal proteinase inhibitor II was the first NMR structure of a globular protein, tendamistat the first "high resolution" NMR structure of a protein, metallothionein the first NMR structure of a metalloprotein, the Antennapedia homeodomain–BS2 operator complex the first NMR structure determination of a protein–DNA complex, and the cyclosporin A–cyclophilin A system was of special interest for the field of immune suppression. Prion proteins (PrP) have become a major research focus of the Wüthrich laboratory since 1994, which resulted in the first three-dimensional structure obtained for this class of proteins in 1996 (3), and subsequent structure determinations of a selected group of mammalian and non-mammalian prion proteins, including those from man, cattle (4) and chicken, which now provide a framework for continued investigations of molecular aspects of the onset and the interspecies transmission of transmissible spongiform encephalopathies. NMR characterization of biological macromolecules has further gone beyond three-dimensional structure determination (see K. Wüthrich, NMR in Structural Biology, World Scientific, Singapore, 1995): Wüthrich's NMR studies of the electronic structure of the prosthetic groups in hemoproteins were surveyed in 1970 in a "citation classic" (Current Contents 31, Nr. 43, p. 19, October 24, 1988). Investigations of biomacromolecular dynamics and conformational equilibria include studies of aromatic ring flips (5), single-site investigations of amide proton exchange, and the structural and kinetic characterization of hydration water in proteins and nucleic acids in solution by high resolution NMR (6), and studies on the role of hydration waters in protein–DNA recognition (7). Work on the protein folding problem includes the introduction of techniques for complete resonance assignment and structure determination of unfolded globular proteins, and NMR approaches for structural characterization of chaperonine-bound substrate proteins. The introduction of transverse relaxation-optimized spectroscopy (TROSY) in 1997 (8) has made a wide spectrum of novel NMR experiments available for studies of biomacromolecular structures in solution. Among the new structural insights that have so far resulted from the use of TROSY-based technology in Wüthrich's laboratory are the discovery of scalar spin–spin couplings across the Watson-Crick hydrogen bonds in DNA (9), complete backbone NMR assignments for proteins in the size range 50-120 kDa (10), structure determinations of small membrane proteins reconstituted in water-soluble micelles (11), and data on intermolecular contacts, dynamics and other aspects of the conformational states of individual macromolecular components in supramolecular structures with molecular weights in the range up to 800 kDa (12 and unpublished).

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 (Nature N&V, 296, 489, 1982).

3.     Riek R., Hornemann, S., Wider, G., Billeter, M., Glockshuber, R. and Wüthrich, K. (1996). Nature 382, 180–182.
NMR structure of the mouse prion protein domain PrP(121–231).

4.     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.

5.     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 (Nature N&V, 258, 112, 1975).

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

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

8.     Pervushin, K., Riek, R., Wider, G. and Wüthrich, K. (1997). Proc. Natl. Acad. Sci. 94, 12366– 12371.
Attenuated T₂ 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.

9.    Pervushin, K., Ono, A., Fernandez, C., Szyperski, T., Kainosho, M. and Wüthrich, K. (1998). Proc. Natl. Acad. Sci. USA 95, 14147–14151.
NMR scalar couplings across Watson–Crick base pair hydrogen bonds in DNA observed by transverse relaxation-optimized spectroscopy.

10.   Salzmann, M., Pervushin, K., Wider, G., Senn, H. and Wüthrich, K. (2000). J. Am. Chem. Soc. 122, 7543–7548.
NMR assignment and secondary structure determination of an octameric 110 kDa protein using TROSY in triple resonance experiments.

11.   Fernandéz, C., Adeishvili, K. and Wüthrich, K. (2001). Proc. Natl. Acad. Sci. USA 98, 2358–2363.
Transverse relaxation-optimized NMR spectroscopy with the outer membrane protein OmpX in dihexanoyl phosphatidylcholine micelles.

12.   Riek, R., Wider, G., Pervushin, K. and Wüthrich, K. (1999). Proc. Natl. Acad. Sci. USA 96, 4918–4923.
Polarization transfer by cross-correlated relaxation in solution NMR with very large molecules.

TH, 11-22-2001