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Loop dynamics and the evolution of enzyme activity

Nature Reviews Chemistry volume 7, pages 536–547 (2023)Cite this article

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A Publisher Correction to this article was published on 20 June 2023

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Abstract

In the early 2000s, Tawfik presented his ‘New View’ on enzyme evolution, highlighting the role of conformational plasticity in expanding the functional diversity of limited repertoires of sequences. This view is gaining increasing traction with increasing evidence of the importance of conformational dynamics in both natural and laboratory evolution of enzymes. The past years have seen several elegant examples of harnessing conformational (particularly loop) dynamics to successfully manipulate protein function. This Review revisits flexible loops as critical participants in regulating enzyme activity. We showcase several systems of particular interest: triosephosphate isomerase barrel proteins, protein tyrosine phosphatases and β-lactamases, while briefly discussing other systems in which loop dynamics are important for selectivity and turnover. We then discuss the implications for engineering, presenting examples of successful loop manipulation in either improving catalytic efficiency, or changing selectivity completely. Overall, it is becoming clearer that mimicking nature by manipulating the conformational dynamics of key protein loops is a powerful method of tailoring enzyme activity, without needing to target active-site residues.

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Fig. 1: Exploiting protein loop dynamics in protein evolution and engineering.
Fig. 2: Overview of the key enzymes regulating tryptophan biosynthesis158, and the complex loop dynamics involved in the process.
Fig. 3: Loop dynamics and enzyme catalysis in protein tyrosine phosphatases.
Fig. 4: Enhancing the luminescence of enzymes from haloalkane dehalogenase and luciferase families with engineered loop dynamics53,161,162.

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Acknowledgements

This work was supported by the Knut and Alice Wallenberg Foundation (grant numbers 2018.0140 and 2019.0431). We thank R. Sterner and S. Osuna for providing high-resolution artwork components for Fig. 2.

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  1. Gaspar P. Pinto

    Present address: Cortex Discovery GmbH, Regensburg, Germany

  2. These authors contributed equally: Marina Corbella, Gaspar P. Pinto.

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  1. Department of Chemistry, Uppsala University, Uppsala, Sweden

    Marina Corbella, Gaspar P. Pinto & Shina C. L. Kamerlin

  2. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA

    Shina C. L. Kamerlin

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Corbella, M., Pinto, G.P. & Kamerlin, S.C.L. Loop dynamics and the evolution of enzyme activity. Nat Rev Chem 7, 536–547 (2023). https://doi.org/10.1038/s41570-023-00495-w

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