Abstract:
:The field of chemical site-selective modification of proteins has progressed extensively in recent decades to enable protein functionalization for imaging, drug delivery, and functional studies. In this Perspective, we provide detailed insight into an alternative use of site-selective protein chemistry to probe the role(s) of unpaired Cys residues in the structure and function of disease relevant proteins. Phosphatases are important players in the successful infection of pathogenic bacteria, which represent a significant health burden, particularly in multi-drug-resistant strains. Therefore, a strategy for readily probing the key amino acid role(s) in structure and function may facilitate the targeting and inhibition of these virulence factors. With a dehydroalanine-based posttranslational chemical mutagenesis approach, it is possible to reveal hitherto unknown function(s) of noncatalytic Cys residues and confirm their role and interplay in pathogenic bacterial phosphatases. By selectively modifying reactive sulfhydryl side chains in different protein local environments, this posttranslational site-selective chemical mutagenesis approach reveals structural information about binding pockets and regulatory roles of the modified residues, which can be further validated by conventional site-directed mutagenesis. Ultimately, these new binding pockets can serve as templates for enhanced structure-based drug design platforms and aid the development of potent and specific inhibitors.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Bertoldo JB,Terenzi H,Hüttelmaier S,Bernardes GJLdoi
10.1021/acs.biochem.8b00639subject
Has Abstractpub_date
2018-10-30 00:00:00pages
6144-6152issue
43eissn
0006-2960issn
1520-4995journal_volume
57pub_type
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