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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1rgq
Original Entry
Title:
Virus/viral protein, hydrolase
Compound:
Ns3 protease
Mutant:
No
UniProt/Swiss-Prot:
O36579-O36579_9HEPC
O39914-O39914_9HEPC
EC Class:
3.4.21.98
Other CSA Entries:
Overview of all sites for 1rgq
Homologues of 1rgq
Entries for UniProt/Swiss-Prot: O36579
Entries for UniProt/Swiss-Prot: O39914
Entries for EC: 3.4.21.98
Other Databases:
PDB entry: 1rgq
PDBsum entry: 1rgq
UniProt/Swiss-Prot: O36579
UniProt/Swiss-Prot: O39914
IntEnz entry: 3.4.21.98
Literature Report:
Introduction:
Hepatitis 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.
Mechanism:
Hepatitis 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.
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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 60 1083Sidechain
Acid/baseWater
Acid/baseSubstrate
Acid/baseResidue
Deprotonates 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.
Evidence from paper Evidence concerns Evidence type
PubMed ID 8861917 Current protein Structural similarity to homologue of known mechanism
PubMed ID 10702283 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ASPA 84 1107Sidechain
ElectrostaticResidue
Modifies the pKa of His 60, allowing it to deprotonate Ser 142.
Evidence from paper Evidence concerns Evidence type
PubMed ID 8861917 Current protein Structural similarity to homologue of known mechanism
PubMed ID 10702283 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLYA 140 1163Backbone amide
ElectrostaticTransition state
Backbone NH forms part of oxyanion hole that stabilises the tetrahedral intermediate and associated transition state.
Evidence from paper Evidence concerns Evidence type
PubMed ID 8861917 Current protein Structural similarity to homologue of known mechanism
PubMed ID 10702283 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
SERA 142 1165Sidechain, Backbone amide
NucleophileSubstrate
ElectrostaticTransition state
Side 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.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10702283 Current protein Residue is covalently bound to intermediate, based on structural data
PubMed ID 8861917 Current protein Structural similarity to homologue of known mechanism
PubMed ID 10702283 Current protein Residue is positioned appropriately (ligand position known)
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.
References:
1
Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.
J. L. Kim and K. A. Morgenstern and C. Lin and T. Fox and M. D. Dwyer and J. A. Landro and S. P. Chambers and W. Markland and C. A. Lepre and E. T. O'Malley and S. L. Harbeson and C. M. Rice and M. A. Murcko and P. R. Caron and J. A. Thomson
Cell 87, (2) 343-55, (1996).
8861917
2
Inhibition of the hepatitis C virus NS3/4A protease. The crystal structures of two protease-inhibitor complexes.
S. Di Marco and M. Rizzi and C. Volpari and M. A. Walsh and F. Narjes and S. Colarusso and R. De Francesco and V. G. Matassa and M. Sollazzo
J Biol Chem 275, (10) 7152-7, (2000).
10702283
3
Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure.
Y. Liu and V. S. Stoll and P. L. Richardson and A. Saldivar and J. L. Klaus and A. Molla and W. Kohlbrenner and W. M. Kati
Arch Biochem Biophys 421, (2) 207-16, (2004).
14984200
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