Long-Range Interactions Within a Nonnative Protein

Science  01 Mar 2002:
Vol. 295, Issue 5560, pp. 1719-1722
DOI: 10.1126/science.1067680

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Protein folding and unfolding are coupled to a range of biological phenomena, from the regulation of cellular activity to the onset of neurodegenerative diseases. Defining the nature of the conformations sampled in nonnative proteins is crucial for understanding the origins of such phenomena. We have used a combination of nuclear magnetic resonance (NMR) spectroscopy and site-directed mutagenesis to study unfolded states of the protein lysozyme. Extensive clusters of hydrophobic structure exist within the wild-type protein even under strongly denaturing conditions. These clusters involve distinct regions of the sequence but are all disrupted by a single point mutation that replaced residue Trp62 with Gly located at the interface of the two major structural domains in the native state. Thus, nativelike structure in the denatured protein is stabilized by the involvement of Trp62 in nonnative and long-range interactions.

  • * Present address: Institute for Software Research International, Carnegie Mellon University, Wean Hall 4604, Pittsburgh, PA 15213, USA.

  • Present address: Johann Wolfgang Goethe-University, Center for Biological Magnetic Resonance, Institute for Organic Chemistry, Marie-Curie-Strasse 11, D-60439 Frankfurt am Main, Germany.

  • Present address: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.

  • § To whom correspondence should be addressed. E-mail: schwalbe{at}

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