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.
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