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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 1rgq

E.C. nameRNA-directed RNA polymerase
SpeciesHepatitis c virus (Virus)
E.C. Number (IntEnz) 2.7.7.48
CSA Homologues of 1rgqThere are 34 Homologs
CSA Entries With UniProtID P27958
CSA Entries With EC Number 2.7.7.48
PDBe Entry 1rgq
PDBSum Entry 1rgq
MACiE Entry 1rgq

Literature Report

IntroductionHepatitis C virus has an RNA genome encoding a single polyprotein. This polyprotein includes a serine protease, NS3, which is required for processing of part of the polyprotein. Specifically, NS3 catalyses cleavage of the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B segment junctions; NS3/NS4A cleavage probably occurs in cis with the remaining cleavages occurring in trans. The NS3 protease associates with the NS4A polypeptide which functions to activate the protease activity.
MechansimHepatitis C virus NS3 protease employs a classical serine protease mechanism. Ser 142 acts as a nucleophile to attack the peptide bond and form a tetrahedral intermediate that is stabilised by the backbone NH of Ser 142 and Gly 140. His 60 promotes the nucleophilic attack by deprotonating Ser 142, while Asp 84 functions to modify the pKa of His 60. Collapse of the tetrahedral intermediate with protonation of the departing amine leaving group by His 60 generates an acyl-enzyme intermediate. This is then hydrolysed by a water molecule that is deprotonated by His 60.
Reaction

Catalytic Sites for 1rgq

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
SerA1421165macie:sideChainSide chain OH acts as a nucleophile to attack the peptide carbonyl. Backbone NH forms part of the oxyanion hole that stabilises the tetrahedral intermediate and associated transition state.
SerA1421165macie:mainChainAmideSide chain OH acts as a nucleophile to attack the peptide carbonyl. Backbone NH forms part of the oxyanion hole that stabilises the tetrahedral intermediate and associated transition state.
GlyA1401163macie:mainChainAmideBackbone NH forms part of oxyanion hole that stabilises the tetrahedral intermediate and associated transition state.
HisA601083macie:sideChainDeprotonates Ser 142 as Ser 142 attacks the peptide bond. Protonates the departing amine leaving group. Deprotonates the water molecule that attacks the acyl-enzyme intermediate.
AspA841107macie:sideChainModifies the pKa of His 60, allowing it to deprotonate Ser 142.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
SerB1421165macie:sideChainSide chain OH acts as a nucleophile to attack the peptide carbonyl. Backbone NH forms part of the oxyanion hole that stabilises the tetrahedral intermediate and associated transition state.
SerB1421165macie:mainChainAmideSide chain OH acts as a nucleophile to attack the peptide carbonyl. Backbone NH forms part of the oxyanion hole that stabilises the tetrahedral intermediate and associated transition state.
GlyB1401163macie:mainChainAmideBackbone NH forms part of oxyanion hole that stabilises the tetrahedral intermediate and associated transition state.
HisB601083macie:sideChainDeprotonates Ser 142 as Ser 142 attacks the peptide bond. Protonates the departing amine leaving group. Deprotonates the water molecule that attacks the acyl-enzyme intermediate.
AspB841107macie:sideChainModifies the pKa of His 60, allowing it to deprotonate Ser 142.

Literature References

Notes:The numbering used in the PDB file is shifted by 3 relative to that used in the literature, where the catalytic residues are referred to as Ser 139, His 57, Asp 81 and Gly 137.
Kim JL
Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.
Cell 1996 87 343-355
PubMed: 8861917
Di Marco S
Inhibition of the hepatitis C virus NS3/4A protease. The crystal structures of two protease-inhibitor complexes.
J Biol Chem 2000 275 7152-7157
PubMed: 10702283
Liu Y
Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure.
Arch Biochem Biophys 2004 421 207-216
PubMed: 14984200
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