Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.
An estimated 1% of the global human population is infected by hepatitis C viruses (HCVs), and there are no broadly effective treatments for the debilitating progression of chronic hepatitis C. A serine protease located within the HCV NS3 protein processes the viral polyprotein at four specific sites and is considered essential for replication. Thus, it emerges as an attractive target for drug design. We report here the 2.5 angstrom resolution X-ray crystal structure of the NS3 protease domain complexed with a synthetic NS4A activator peptide. The protease has a chymotrypsin-like fold and features a tetrahedrally coordinated metal ion distal to the active site. The NS4A peptide intercalates within a beta sheet of the enzyme core.
Kim
J L
JL
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139-4242, USA.
Morgenstern
K A
KA
Lin
C
C
Fox
T
T
Dwyer
M D
MD
Landro
J A
JA
Chambers
S P
SP
Markland
W
W
Lepre
C A
CA
O'Malley
E T
ET
Harbeson
S L
SL
Rice
C M
CM
Murcko
M A
MA
Caron
P R
PR
Thomson
J A
JA
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D016174:Hepacivirus / Q000201:enzymology*; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D013379:Substrate Specificity; D017361:Viral Nonstructural Proteins / Q000378:metabolism / Q000648:ultrastructure*; D015032:Zinc; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D046911:Macromolecular Substances; D017361:Viral Nonstructural Proteins; D015032:Zinc; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus