Cys145

Cys145 is a designation used in protein chemistry to refer to a cysteine residue at position 145 within a given protein sequence. The specific role and importance of Cys145 depend on the protein context, and numbering is defined by the protein’s amino acid sequence.

In the SARS-CoV-2 main protease (also known as 3CLpro or Mpro), Cys145 is the catalytic nucleophile in the enzyme’s active site and forms part of the catalytic dyad with His41. The thiol group of Cys145 engages in a nucleophilic attack on the peptide bond of substrate proteins, enabling proteolytic cleavage essential for viral polyprotein processing. This mechanism is facilitated by surrounding residues and solvent molecules that assist in proton transfer and stabilization of reaction intermediates. The reactivity of Cys145 is influenced by its local microenvironment, including the pKa of the thiol group.

Cys145 is a critical functional residue; altering it through mutation or chemical modification typically abolishes or markedly reduces protease activity. Because of its central role in catalysis, Cys145 is a prominent target in antiviral drug design. Inhibitors that covalently modify Cys145 or block its access to substrates have been explored, including covalent and noncovalent scaffolds designed to disrupt protease function.

Beyond the viral protease example, Cys145 can occur in other proteins with context-dependent roles. As with other cysteine residues, its chemical reactivity can be influenced by oxidation state and the local three-dimensional environment, which in turn affect potential disulfide formation, redox sensing, or participation in catalytic mechanisms.