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Allosteric inhibition through suppression of transient conformational states

Nature Chemical Biology volume 9, pages 462–465 (2013)Cite this article

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Abstract

The ability to inhibit binding or enzymatic activity is key to preventing aberrant behaviors of proteins. Allosteric inhibition is desirable as it offers several advantages over competitive inhibition, but the mechanisms of action remain poorly understood in most cases. Here we show that allosteric inhibition can be effected by destabilizing a low-populated conformational state that serves as an on-pathway intermediate for ligand binding, without altering the protein's ground-state structure. As standard structural approaches are typically concerned with changes in the ground-state structure of proteins, the presence of such a mechanism can go easily undetected. Our data strongly argue for the routine use of NMR tools suited to detect and characterize transiently formed conformational states in allosteric systems. Structure information on such important intermediates can ultimately result in more efficient design of allosteric inhibitors.

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Figure 1: CAP* transiently populates the active DBD state.
Figure 2: Energy landscape of CAP* and its manipulation by the inhibitor.
Figure 3: Structural characterization of CAP* and CAP*–cGMP2.
Figure 4: Allosteric inhibition by suppressing an on-pathway transiently populated intermediate.

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Acknowledgements

This work was supported by the US National Science Foundation grant MCB1121896 to C.G.K.

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Authors and Affiliations

  1. Center for Integrative Proteomics Research, Rutgers University, Piscataway, New Jersey, USA

    Shiou-Ru Tzeng & Charalampos G Kalodimos

  2. Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, New Jersey, USA

    Shiou-Ru Tzeng & Charalampos G Kalodimos

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  1. Shiou-Ru Tzeng
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Contributions

S.-R.T. and C.G.K. conceived the project. S.-R.T. and C.G.K. designed the experiments. S.-R.T. performed all of the experiments. S.-R.T. and C.G.K. analyzed and interpreted the data and wrote the manuscript.

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Correspondence to Charalampos G Kalodimos.

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The authors declare no competing financial interests.

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Tzeng, SR., Kalodimos, C. Allosteric inhibition through suppression of transient conformational states. Nat Chem Biol 9, 462–465 (2013). https://doi.org/10.1038/nchembio.1250

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