Research Article

Redox-based reagents for chemoselective methionine bioconjugation

See allHide authors and affiliations

Science  10 Feb 2017:
Vol. 355, Issue 6325, pp. 597-602
DOI: 10.1126/science.aal3316

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Targeting proteins at the other sulfur

As the only amino acid with a thiol (SH) group, cysteine is easily targeted for site-selective protein modifications. Hydrophobic methionine also has sulfur in its side chain, but its capping methyl group has hindered analogous targeting efforts. Lin et al. introduce a complementary protocol to tether new substituents exclusively to methionine, even in the presence of cysteine. They used an oxaziridine group as an oxidant to form sulfimide (S=N) linkages. The approach allowed antibody-drug conjugation and chemoproteomic screening for reactive methionine surface residues.

Science, this issue p. 597

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.

View Full Text