Cysteine proteases of positive strand RNA viruses and chymotrypsin‐like serine proteases

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Abstract
Evidence is presented, based on sequence comparison and secondary structure prediction, of structural and evolutionary relationship between chymotrypsin‐like serine proteases, cysteine proteases of positive strand RNA viruses (3C proteases of picornaviruses and related enzymes of como‐, nepo‐ and potyviruses) and putative serine protease of a sobemovirus. These observations lead to re‐identification of principal catalytic residues of viral proteases. Instead of the pair of Cys and His, both located in the C‐terminal part of 3C proteases, a triad of conserved His, Asp(Glu) and Cys(Ser) has been identified, the first two residues resident in the N‐terminal, and Cys in the C‐terminal β‐barrel domain. These residues are suggested to form a charge‐transfer system similar to that formed by the catalytic triad of chymotrypsin‐like proteases. Based on the structural analogy with chymotrypsin‐like proteases, the His residue previously implicated in catalysis, together with two partially conserved Gly residues, is predicted to constitute part of the substrate‐binding pocket of 3C proteases. A partially conserved ThrLys/Arg dipeptide located in the loop preceding the catalytic Cys is suggested to confer the primary cleavage specificity of 3C toward Glx/Gly(Ser) sites. These observations provide the first example of relatedness between proteases belonging, by definition, to different classes.