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A protein functionalization platform based on selective reactions at methionine residues

Naturevolume 562pages563568 (2018) | Download Citation

Abstract

Nature has a remarkable ability to carry out site-selective post-translational modification of proteins, therefore enabling a marked increase in their functional diversity1. Inspired by this, chemical tools have been developed for the synthetic manipulation of protein structure and function, and have become essential to the continued advancement of chemical biology, molecular biology and medicine. However, the number of chemical transformations that are suitable for effective protein functionalization is limited, because the stringent demands inherent to biological systems preclude the applicability of many potential processes2. These chemical transformations often need to be selective at a single site on a protein, proceed with very fast reaction rates, operate under biologically ambient conditions and should provide homogeneous products with near-perfect conversion2,3,4,5,6,7. Although many bioconjugation methods exist at cysteine, lysine and tyrosine, a method targeting a less-explored amino acid would considerably expand the protein functionalization toolbox. Here we report the development of a multifaceted approach to protein functionalization based on chemoselective labelling at methionine residues. By exploiting the electrophilic reactivity of a bespoke hypervalent iodine reagent, the S-Me group in the side chain of methionine can be targeted. The bioconjugation reaction is fast, selective, operates at low-micromolar concentrations and is complementary to existing bioconjugation strategies. Moreover, it produces a protein conjugate that is itself a high-energy intermediate with reactive properties and can serve as a platform for the development of secondary, visible-light-mediated bioorthogonal protein functionalization processes. The merger of these approaches provides a versatile platform for the development of distinct transformations that deliver information-rich protein conjugates directly from the native biomacromolecules.

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The data that support the findings of this study are available within the paper and its Supplementary Information. Raw data are available from the corresponding author on reasonable request.

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Acknowledgements

We thank M. Nappi and C. Guerot for advice and useful discussions. We thank the Marie Curie Actions program (M.T.T. and M.G.S.), AstraZeneca and EPRSC (J.E.N.), and the European Research Council (ERC-SRG-259711), EPSRC (EP/100548X/1) and the Royal Society (Wolfson Merit Award) for fellowships (M.J.G.). We are grateful to J. Chin, N. Huguen, M. Skehel, H. Lewis and M. Edgeworth for assistance with protein purification and mass spectrometry experiments.

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Nature thanks A. Spokoyny and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Affiliations

  1. Department of Chemistry, University of Cambridge, Cambridge, UK

    • Michael T. Taylor
    • , Jennifer E. Nelson
    • , Marcos G. Suero
    •  & Matthew J. Gaunt

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Contributions

M.J.G., M.T.T., J.E.N. and M.G.S. conceived the project and designed the experiments. M.J.G., M.T.T., J.E.N. and M.G.S. performed and analysed the experiments. M.J.G., M.T.T. and J.E.N. wrote the paper.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Matthew J. Gaunt.

Supplementary information

  1. Supplementary Information

    This file contains Supplementary Text, which includes Supplementary Figs. S1–S83 and Supplementary Tables S1–S8.

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https://doi.org/10.1038/s41586-018-0608-y

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