Hepaciviruses [E1] and pegiviruses [E2] are two genera of the viral family
Flaviviridae [E3]. Both the Hepacivirus and Pegivirus genera contain species
that infect humans. Hepatitis C is a disease caused by the hepatitis C virus
(HCV), a hepacivirus that is one of the most important causes of severe
chronic liver disease. Human pegivirus (HPgV) is the most closely related
human virus to HCV. HPgV is a lymphotropic virus but unlike HCV it has little,
if any, associated pathogenicity in humans. The genome structures of
hepaciviruses and pegiviruses are conserved and share many similarities. Both
genera are single-stranded positive sense RNA viruses and their genomes encode
large polyproteins, which are cleaved into structural and nonstructural (NS)
proteins through the action of cellular peptidases as well as the viral-encoded proteases including NS3/4A. NS3 contains Ser protease and RNA helicase
activities that require its cofactor NS4A. The NS3 protease domain resides in
the N-terminal one third of the NS3 protein whereas the C-terminal two-third
contain a helicase (see <PDOC51192>). The NS3/A4 protease is not only
essential for generating mature viral proteins required for viral replication,
but also hydrolyzes proteins, which are part of the innate immune system,
thereby confounding the innate immune response to viral infection [1,2,3,4,5].
The Hepacivirus/Pegivirus NS3 protease domain forms the peptidase family
S29 (hepacivirin family) of clan PA [E4].
The Hepacivirus/Pegivirus NS3 protease domain folds as a trypsin-like
proteinase with two six-stranded β barrels and a catalytic triad of His,
Asp, Ser (see <PDB:1A1Q>). It exhibits some features that are highly unusual
for a trypsin-like proteinase: it is covalently attached to a helicase
possessing NTPase activity, it requires a protein cofactor (NS4A), and
displays sensitivity to metal ions .
The profile we developed covers the entire Hepacivirus/Pegivirus NS3 protease
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