Spying On Fleeting Proteins

Protein intermediates—fleeting structures that are here one millisecond and gone the next—are very difficult to observe. But a way to visualize some of them has been found by Lewis E. Kay of the University of Toronto; Alan R. Fersht of the Medical Research Council Centre for Protein Engineering, in Cambridge, England; and coworkers. The technique combines nuclear magnetic resonance relaxation dispersion spectroscopy with CS-Rosetta, a chemical-shift-based method for structure elucidation. The researchers demonstrated the approach by using it to structurally analyze, at atomic resolution, an intermediate on the folding pathway of an FF domain, a common protein motif. However, the method “is not restricted to folding intermediates but ­includes excited states important for function—for example, enzyme catalysis and ligand binding,” they write in Science (2010, 329, 1312). In an accompanying commentary, Hashim M. Al-Hashimi of the University of Michigan notes that the study ushers in “a new era in which researchers can determine the high-resolution structure of the excited states of proteins. … It seems inevitable that the entire protein structure landscape will soon succumb to NMR and computation.”