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Catalytic Site Atlas

CSA LITERATURE entry for 1cqq

E.C. nameRNA-directed RNA polymerase
SpeciesHuman rhinovirus 2 (Virus)
E.C. Number (IntEnz) 2.7.7.48
CSA Homologues of 1cqqThere are 10 Homologs
CSA Entries With UniProtID P04936
CSA Entries With EC Number 2.7.7.48
PDBe Entry 1cqq
PDBSum Entry 1cqq
MACiE Entry 1cqq

Literature Report

IntroductionThe human rhinovirus 3C is a cysteine protease that is essential for the processing of the viral precursor polyprotein and release of RNA replication proteins. The enzyme is related by amino acid sequence to the trypsin-like serine proteases, and is a member of a novel group of cysteine proteases with a serine protease-like fold.
MechansimIn rhinovirus 3C, the catalytically important residues Cys147, His50 and Glu71 form a triad related to that of the serine proteases. The highly conserved sequence Gly-X-Cys-Gly-Gly in viral C3 proteases serves to orientate the Cys147 for nucleophilic attack at the substrate carbonyl. Residue backbone amide groups are positioned to stabilise the anionic tetrahedral intermediate as part of an oxyanion hole. This resembles the mechanism of the serine protease family, suggesting more closely related mechanism to this class of enzymes, rather than that of the cysteine proteases.
Reaction

Catalytic Sites for 1cqq

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
CysA1471654macie:sideChainThe residue acts as a nucleophile towards the polypeptide substrate. Hydrogen bonding interactions with His40 allow the proton to be transferred from Cys147 to the N terminus of the cleaved polypeptide with collapse of the anionic intermediate. The resulting acyl-enzyme intermediate is then hydrolysed by water, regenerating the free Cys147 and therefore the active site.
The backbone amide is also implicated in forming part of the oxyanion hole, stabilising the anionic intermediate.
CysA1471654macie:mainChainAmideThe residue acts as a nucleophile towards the polypeptide substrate. Hydrogen bonding interactions with His40 allow the proton to be transferred from Cys147 to the N terminus of the cleaved polypeptide with collapse of the anionic intermediate. The resulting acyl-enzyme intermediate is then hydrolysed by water, regenerating the free Cys147 and therefore the active site.
The backbone amide is also implicated in forming part of the oxyanion hole, stabilising the anionic intermediate.
HisA401547macie:sideChainhe residue is hydrogen bonded to the nucleophilic Cys147. It acts as a proton acceptor in the anionic transition state, and then relays the proton to the departing N terminus of the cleaved peptide after the collapse of the tetrahedral intermediate. It also activates the hydrolytic water for attack at the acyl-enzyme intermediate. Hydrogen bonding interactions with Glu71 enhance the residue's acid/base function.
GluA711578macie:sideChainThe residue hydrogen bonds to the N(E) atom of His 40, modifying the pKa of the N(delta) atom of the imidazole ring, which is in turn implicated in proton transfer between the nucleophilic Cys147 and substrate.
GlyA1451652macie:mainChainAmideThe residue's backbone forms part of the oxyanion hole which stabilises the anionic tetrahedral intermediate.

Literature References

Notes:
Matthews DA
Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes.
Proc Natl Acad Sci U S A 1999 96 11000-11007
PubMed: 10500114
Cheah KC
Site-directed mutagenesis suggests close functional relationship between a human rhinovirus 3C cysteine protease and cellular trypsin-like serine proteases.
J Biol Chem 1990 265 7180-7187
PubMed: 2158990
Matthews DA
Structure of human rhinovirus 3C protease reveals a trypsin-like polypeptide fold, RNA-binding site, and means for cleaving precursor polyprotein.
Cell 1994 77 761-771
PubMed: 7515772
Spirt MJ.
Complicated intra-abdominal infections: a focus on appendicitis and diverticulitis.
Postgrad Med 2010 122 39-51
PubMed: 20107288
Gosert R
Identification of active-site residues in protease 3C of hepatitis A virus by site-directed mutagenesis.
J Virol 1997 71 3062-3068
PubMed: 9060667
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