Accessible cysteine residues across multiple cellular proteins

Accessible cysteine residues across multiple cellular proteins represent a broad class of reactive thiol groups that serve as critical sites for both endogenous post-translational modifications and exogenous covalent drug interactions (Backus et al., 2016, Nature). These residues are characterized by their nucleophilicity, which is often enhanced by the local protein environment, making them susceptible to modification by electrophilic molecules (Weerapana et al., 2010, Nature). Biologically, these cysteines are involved in essential processes such as redox sensing, catalytic activity in enzymes like proteases and phosphatases, and the formation of disulfide bonds for structural integrity (PubChem, Cysteine). In the context of pharmacology, targeting specific accessible cysteines has led to the development of highly potent, irreversible inhibitors for various diseases, most notably in oncology with drugs targeting kinases like EGFR and BTK (Resnick et al., 2017, J. Med. Chem.). However, because many proteins contain reactive cysteines, achieving selectivity is a major challenge, and non-specific binding can lead to toxicity or immunogenic reactions (NIH, Covalent Inhibitors). This cysteineome approach is frequently used in activity-based protein profiling (ABPP) to identify novel druggable pockets across the proteome.

Other names

Reactive cysteinesNucleophilic cysteinesProtein thiolsCysteineome

Covalent modification of the cysteine thiol group, typically via Michael addition or nucleophilic substitution, leading to irreversible or slowly reversible inhibition of the protein's function (Backus et al., 2016, Nature).