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  2. Redox-based reagents for chemoselective methionine bioconjugation

Redox-based reagents for chemoselective methionine bioconjugation

  • Science. 2017 Feb 10;355(6325):597-602. doi: 10.1126/science.aal3316.
Shixian Lin 1 Xiaoyu Yang 1 2 Shang Jia 1 Amy M Weeks 3 Michael Hornsby 3 Peter S Lee 3 Rita V Nichiporuk 4 Anthony T Iavarone 4 James A Wells 3 5 F Dean Toste 6 7 Christopher J Chang 6 8 9 7
Affiliations

Affiliations

  • 1 Department of Chemistry, University of California, Berkeley, CA, USA.
  • 2 School of Physical Science and Technology, ShanghaiTech University, Shanghai, China.
  • 3 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
  • 4 California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA.
  • 5 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.
  • 6 Department of Chemistry, University of California, Berkeley, CA, USA. chrischang@berkeley.edu fdtoste@berkeley.edu.
  • 7 Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • 8 Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
  • 9 Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
Abstract

Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug conjugates and proteomics. In contrast, selective ligation to the Other sulfur-containing amino acid, methionine, has been precluded by its intrinsically weaker nucleophilicity. Here, we report a strategy for chemoselective methionine bioconjugation through redox reactivity, using oxaziridine-based reagents to achieve highly selective, rapid, and robust methionine labeling under a range of biocompatible reaction conditions. We highlight the broad utility of this conjugation method to enable precise addition of payloads to proteins, synthesis of antibody-drug conjugates, and identification of hyperreactive methionine residues in whole proteomes.

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