Viruses in the order Picornavirales infect different vertebrate, invertebrate, and plant hosts and are responsible for a variety of human, animal, and plant diseases. Viruses in this order have a single-stranded, positive sense RNA (+ssRNA) genome that generally translates a large precusrsor polyprotein. After translation, the viral precursor polyprotein is proteolytically cleaved to generate mature functional viral proteins. This maturation process is usually mediated by (more than one) proteases, and a 3C (for the family Picornaviridae) or 3C-like (3CL) protease (for other families) plays a central role in the cleavage of the viral precursor polyprotein. In addition to its key role in processing the polyprotein, 3C/3C-like protease is able to cleave a number of host proteins to remodel the cellular environment for virus reproduction [1,2,3,4,5,6]. The Picornavirales 3C/3C-like protease domain forms the peptidase family C3 (picornain family) of clan PA [E1].

The 3C/3CL protease domain adopts a chymotrypsin-like fold with a cysteine nucleophile in place of a commonly found serine. Accordingly, 3C and 3C-like proteases partially tolerate a replacement of the catalytic cysteine by a serine, and vice-versa, suggesting that the cysteine and serine perform an analogous catalytic function. The catalytic triad is made of a histidine, an aspartate/glutamate and the conserved cysteine in this sequential order. The 3C/3CL protease domain folds into two antiparallel β barrels that are linked by a loop with a short α-helix in its middle, and flanked by two other α-helices at the N- and C-termini (see <PDB:3Q3X>). The two barrels are topologically equivalent and are formed by six antiparallel β strands with the first four organized into a Greek key motif. The active-site residues are located in the cleft between the two barrels with the nucleophilic Cys from the C-terminal barrel and the general acid base His-Glu/Asp from the N-terminal barrel [1,2,4].

The profile we developed covers the entire 3C/3C-like protease domain.