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Protein dynamics

Catch them if you can

Nature Chemical Biology volume 9, pages 410–411 (2013)Cite this article

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A Corrigendum to this article was published on 17 June 2013

This article has been updated

NMR analysis of the conformational energy landscape of the catabolite activator protein suggests that allosteric inhibition can be achieved by blocking access to elusive high-energy states of proteins.

Protein structures populate complex energy landscapes, which include low-energy basins (ground states) and high-energy basins (conformationally excited states) that can be reversibly accessed via thermal fluctuations1. This conformational equilibrium responds to the laws of chemical equilibrium: temperature, pressure and pH as well as mutations and post-translational modifications can shift the populations of the different states, promoting active or inactive conformations2. At ambient temperature, excited states, consisting of locally unfolded or otherwise dynamic conformations, are rarely visited (on the order of 1–10% of the time)3. However, these high-energy states are critical for function and have been implicated as on-pathway intermediates in protein folding and enzyme catalysis, enabling protein-protein recognition, and as preferential targets for small-ligand binding. Because the conformational entropy associated with the free energy of the excited states is higher than that of the ground states, it is not possible to image these states by X-ray crystallography, the gold standard for structural biology. In the past decade, NMR spectroscopists have sharpened their skills to fill this gap, with a goal of catching the excited states in action3. In particular, NMR relaxation dispersion methods are emerging as the tool of choice to identify and characterize the conformational interconversion of proteins between ground and excited states occurring on the μs-to-ms timescale4. Exchange between these conformational states affects frequency, intensity and line widths of the nuclear spin transitions. By quantifying these effects, relaxation dispersion measurements not only report on the population and exchange kinetics of these high energy states but also enable the determination of their three-dimensional structure5.

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Figure 1: Schematic of the conformational energy landscape of CAP*.

Change history

  • 21 May 2013

    In the version of this article initially published online, the imprecise term 'configurational entropy' was used in the middle of the first paragraph. The correct term is 'conformational entropy'. The error has been corrected for the print, PDF and HTML versions of this article.

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  1. Gianluigi Veglia is in the Department of Chemistry and the Department of Biochemistry, Molecular Biology and Biophysics at the University of Minnesota, Minneapolis, Minnesota.

    Gianluigi Veglia

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  1. Gianluigi Veglia
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Correspondence to Gianluigi Veglia.

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The author declares no competing financial interests.

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Veglia, G. Catch them if you can. Nat Chem Biol 9, 410–411 (2013). https://doi.org/10.1038/nchembio.1258

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