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Cited by 354

The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.

A “Tag-and-Modify” Approach to Site-Selective Protein Modification

Chalker, Justin M., Bernardes, Gonçalo J. L., Davis, Benjamin G.·2011·Accounts of Chemical Research
DOI 10.1021/ar200056q
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Abstract

Covalent modification can expand a protein's functional capacity. Fluorescent or radioactive labeling, for instance, allows imaging of a protein in real time. Labeling with an affinity probe enables isolation of target proteins and other interacting molecules. At the other end of this functional spectrum, protein structures can be naturally altered by enzymatic action. Protein-protein interactions, genetic regulation, and a range of cellular processes are under the purview of these post-translational modifications. The ability of protein chemists to install these covalent additions selectively has been critical for elucidating their roles in biology. Frequently the transformations must be applied in a site-specific manner, which demands the most selective chemistry. In this Account, we discuss the development and application of such chemistry in our laboratory. A centerpiece of our strategy is a "tag-and-modify" approach, which entails sequential installation of a uniquely reactive chemical group into the protein (the "tag") and the selective or specific modification of this group. The chemical tag can be a natural or unnatural amino acid residue. Of the natural residues, cysteine is the most widely used as a tag. Early work in our program focused on selective disulfide formation in the synthesis of glycoproteins. For certain applications, the susceptibility of disulfides to reduction was a limitation and prompted the development of several methods for the synthesis of more stable thioether modifications. The desulfurization of disulfides and conjugate addition to dehydroalanine are two routes to these modifications. The dehydroalanine tag has since proven useful as a general precursor to many modifications after conjugate addition of various nucleophiles; phosphorylated, glycosylated, peptidylated, prenylated, and even mimics of methylated and acetylated lysine-containing proteins are all accessible from dehydroalanine. While cysteine is a useful tag for selective modification, unnatural residues present the opportunity for bio-orthogonal chemistry. Azide-, arylhalide-, alkyne-, and alkene-containing amino acids can be incorporated into proteins genetically and can be specifically modified through various transformations. These transformations often rely on metal catalysis. The Cu-catalyzed azide-alkyne addition, Ru-catalyzed olefin metathesis, and Pd-catalyzed cross-coupling are examples of such transformations. In the course of adapting these reactions to protein modification, we learned much about the behavior of these reactions in water, and in some cases entirely new catalysts were developed. Through a combination of these bio-orthogonal transformations from the panel of tag-and-modify reactions, multiple and distinct modifications can be installed on protein surfaces. Multiple modifications are common in natural systems, and synthetic access to these proteins has enabled study of their biological role. Throughout these investigations, much has been learned in chemistry and biology. The demands of selective protein modification have revealed many aspects of reaction mechanisms, which in turn have guided the design of reagents and catalysts that allow their successful deployment in water and in biological milieu. With this ability to modify proteins, it is now possible to interrogate biological systems with precision that was not previously possible.

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Metadata

Authors
Chalker, J. M., Bernardes, G. J. L., & Davis, B. G.
Venue
Accounts of Chemical Research
Publisher
American Chemical Society (ACS)
Published
2011-05-12
Volume
44
Issue
9
Pages
730-741
ISSN
  • 0001-4842 (ISSN-L)
  • 1520-4898
DOI
10.1021/ar200056q
OpenAlex
W1991028037
Cited by
354
References
62
FWCI
14.21
Type
journal article
Language
en
Open access
closed

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