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A protein functionalization platform based on selective reactions at methionine residues

Author

Listed:
  • Michael T. Taylor

    (University of Cambridge)

  • Jennifer E. Nelson

    (University of Cambridge)

  • Marcos G. Suero

    (University of Cambridge)

  • Matthew J. Gaunt

    (University of Cambridge)

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 conversion2–7. 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.

Suggested Citation

  • Michael T. Taylor & Jennifer E. Nelson & Marcos G. Suero & Matthew J. Gaunt, 2018. "A protein functionalization platform based on selective reactions at methionine residues," Nature, Nature, vol. 562(7728), pages 563-568, October.
  • Handle: RePEc:nat:nature:v:562:y:2018:i:7728:d:10.1038_s41586-018-0608-y
    DOI: 10.1038/s41586-018-0608-y
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    Citations

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    Cited by:

    1. Mengzhun Guo & Kai Zhao & Liang Guo & Rui Zhou & Qiuju He & Kuan Lu & Tian Li & Dandan Liu & Jinfeng Chen & Jing Tang & Xin Fu & Jinyun Zhou & Bei Zheng & Samuel I. Mann & Yongdeng Zhang & Jing Huang , 2023. "Copper assisted sequence-specific chemical protein conjugation at a single backbone amide," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Samrat Sahu & Benjamin Emenike & Christian Michel Beusch & Pritha Bagchi & David Ezra Gordon & Monika Raj, 2024. "Copper(I)-nitrene platform for chemoproteomic profiling of methionine," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Luke J. Dowman & Sameer S. Kulkarni & Juan V. Alegre-Requena & Andrew M. Giltrap & Alexander R. Norman & Ashish Sharma & Liliana C. Gallegos & Angus S. Mackay & Adarshi P. Welegedara & Emma E. Watson , 2022. "Site-selective photocatalytic functionalization of peptides and proteins at selenocysteine," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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