Kurt Wüthrich of The Scripps Research Institute wins 2002 Nobel Prize in Chemistry

October 09, 2002

La Jolla, CA, October 9, 2002--Kurt Wüthrich, Ph.D., who is Cecil H. and Ida M. Green Visiting Professor of Structural Biology at The Scripps Research Institute (TSRI) and a member of TSRI's Skaggs Institute for Chemical Biology; and Professor of Biophysics at Eidgenössische Technische Hochschule Zürich (ETHZ), Switzerland, was awarded the 2002 Nobel Prize in Chemistry today for applying the technique of nuclear magnetic resonance (NMR) to solving the structures of biological macromolecules.

Biological macromolecules--the DNA, proteins, sugars, and lipids of life--make up all the important structures of the cell, but they are much too small to study under a microscope. Determining the structure of these macromolecules through NMR was pioneered by Wüthrich and allows scientists to "see" what they look like, to study and probe their structures, and to design drugs that inhibit them. Most recently, NMR structures have been critical in the design of drugs to treat, for instance, cancer and HIV.

"We are thrilled that Dr. Wüthrich has received this recognition," says TSRI President Richard Lerner, M.D. "He is in the forefront of his field and he continues to push the boundaries of structural biology in new and important ways."

Awarded annually by the Royal Swedish Academy of Sciences for achievements in physics, chemistry, medicine, literature, economics, and peace, the prize recognizes individuals who, as stipulated in Alfred Nobel's will, "have conferred the greatest benefit on mankind." Each prize carries a cash award of roughly one million dollars. Last year, K. Barry Sharpless, Ph.D., W.M. Keck Professor of Chemistry at TSRI and member of TSRI's Skaggs Institute for Chemical Biology, was awarded the 2001 Nobel Prize in Chemistry for the development of catalytic asymmetric synthesis.

"Two Nobel Prizes in two years is a remarkable endorsement of what TSRI is about--attracting the very best scientific minds and providing them the resources and freedom they need to produce the very best research," Lerner says. "The prizes also underscore the extraordinary quality of the TSRI structural biology and chemistry programs."

Wüthrich, who currently operates a laboratory at TSRI and is scheduled to become a full-time faculty member in 2004, was awarded half this year's prize in chemistry specifically "for his development of nuclear magnetic resonance spectroscopy for determining the three-dimensional structure of biological macromolecules in solution," according to the Nobel web site. John B. Fenn of the Virginia Commonwealth University in the United States and Koichi Tanaka of the Shimadzu Corporation in Japan share the other half "for their development of soft desorption ionisation methods for mass spectrometric analyses of biological macromolecules."

In 1982, Wüthrich's group published a series of four papers that outlined a framework for NMR structure determination of proteins. In 1984, he published the first protein structure determined by NMR--that of the protein bull seminal protease inhibitor. He is author of the definitive book on the subject, "NMR of Proteins and Nucleic Acids" (1986).

In addition to developing methodology, Wüthrich has devoted his research to solving structures of biological molecules. He has solved more than 50 novel 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. Misfolded prion proteins are believed to be the cause of bovine spongiform encephalopathy, or mad cow disease, and a form of the disease in humans, called variant Creutzfeldt-Jakob Disease.

Wüthrich has solved numerous protein pheromone structures from Mediterranean sea creatures and pheromone-binding proteins from other organisms, such as silkworms. He is also looking at "chaperonin" systems like GroEL--the very large protein complex that monitors the folding of newly synthesized proteins.

He also has been looking at ways of solving membrane protein structures, which are some of the least solved of all the relevant molecular structures in biology. Less than one half of one percent of the structures contained in the Brookhaven National Laboratory Protein Data Bank are of integral membrane proteins, despite the fact that over a third of all proteins in the body are in the membrane.

Most recently, Wüthrich pioneered the new technique of transverse relaxation-optimized spectroscopy NMR (TROSY), which extends several-fold the size limit of structures that can be solved with NMR. This made it possible for the first time for investigators to use NMR to solve many important biological structures--such as large proteins and protein/protein, protein/DNA or protein/lipid complexes--that are impossible to investigate with conventional NMR, which cannot solve structures larger than 50,000 daltons. A dalton is equivalent to the mass of one hydrogen atom.

"We can now do reasonably detailed structural investigations of proteins in structures of size up to about 150,000 daltons," says Wüthrich.

He has also pioneered other techniques, such as cross-correlated relaxation-enhanced polarization transfer (CRINEPT), which when combined with TROSY, result in highly effective experiments for very large structures. "We can go up to one million [daltons], essentially," Wüthrich says.

Wüthrich did his undergraduate training at the University of Bern, Switzerland, receiving a Licentiat in chemistry, physics and mathematics in 1962. In 1964, he was awarded a Ph.D. in chemistry from the University of Basel, Switzerland, (studying with Professor S. Fallab), where he also completed a year of postdoctoral training. After an additional two years of postdoctoral training at the University of California, Berkeley, Wüthrich worked for two years as a member of the technical staff at Bell Telephone Laboratories in Murray Hill, New Jersey. In 1969, he moved to the Eidgenössische Technische Hochschule Zürich (ETHZ), Switzerland, where is currently Professor of Biophysics.

Wüthrich's is a Member of the European Molecular Biology Organization; a Member of the Academia Europaea; a Foreign Associate of the National Academy of Sciences in the United States; an Honorary Fellow of The National Academy of Sciences, India; a Foreign Honorary Member of the American Academy of Arts and Sciences; an Honorary Member of the Japanese Biochemical Society and a Fellow of the American Association for the Advancement of Science.

A Primer on the NMR of Biological Macromolecules
Discovered in 1946 by two physicists working independently--Edward Mills Purcell at Harvard University and Felix Bloch at Stanford University, who shared the 1952 Nobel Prize in physics for their discovery--nuclear magnetic resonance (NMR) refers to the ability of atomic nuclei to reorient themselves in a magnetic field when exposed to radiation of a particular "resonant" frequency in the radio band.

Certain atomic nuclei ("NMR isotopes") contain charged particles with spin, which according to Maxwell's equations, induces a magnetic field. Though small, the magnetic "moments" of these nuclei makes them sensitive to an external magnetic field. In an NMR magnet, the nuclei act like tiny bar magnets and tend to align themselves preferentially in a particular configuration, while also undergoing spinning motions similar to the gyroscopic precessions of bicycle wheels or spinning tops under an external torque.

Any fluctuating magnetic field orthogonal to that of the NMR magnet will perturb the alignment of the nuclear magnetic moments away from the equilibrium configuration, but only if the frequency of the fluctuating field is precisely equal to the precession frequencies of the nuclear magnetic moments. These are called the resonant, or Larmor, frequencies and are proportional to the field strength of the NMR magnet. The Scripps Research Institute's (TSRI's) new 21 tesla magnet, for instance, causes protons to precess at 900 MHz. Movement of atomic nuclei in the NMR as they go in and out of resonance causes small but measurable induced voltages, and it is this signal which is being measured in the NMR experiment.

An NMR spectrometer will scan a broad range of radio frequencies and record all the resonances as a spectrum. Atoms like 1H, 13C, or 15N, which are ubiquitous in proteins and nucleic acids, have a nuclear spin and give rise to NMR signals, whereas atoms like 12C and 16O have no nuclear spin and therefore no signal. Different spectra can be taken with molecules that have been selectively labeled with isotopes that have or do not have a spin.

In an NMR experiment, a sample in a glass tube is inserted into the magnet, and the resonant responses of the atoms in the sample over a range of frequencies are recorded. These responses are influenced by the shape of the molecule in which the atoms reside--by their proximity to other atoms in the molecule. An NMR spectrum is unique for a particular molecule, and the structure of a molecule can be determined from its spectrum.

There is no question that NMR is one of the fundamental techniques in chemistry and biology today. In recognition of that fact, Richard R. Ernst at ETH in Zürich was awarded the 1991 Nobel Prize for Chemistry for "the development of the methodology of high resolution nuclear magnetic resonance (NMR) spectroscopy"--tools that also provided a starting platform for Wüthrich's development of NMR techniques to study biological macromolecules.

Scripps Research Institute

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