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Catalytic Site Atlas

CSA LITERATURE entry for 1nkk

E.C. nameassemblin
SpeciesHuman cytomegalovirus (Human cytomegalovirus)
E.C. Number (IntEnz) 3.4.21.97
CSA Homologues of 1nkkThere are 18 Homologs
CSA Entries With UniProtID P16753
CSA Entries With EC Number 3.4.21.97
PDBe Entry 1nkk
PDBSum Entry 1nkk
MACiE Entry M0238

Literature Report

IntroductionHerpesviruses, such as human cytomegalovirus, are large double stranded DNA viruses that infect most species throughout the animal kingdom. They encode a protease that is essential for production of infectious virons: this enzyme catalyses the maturational processing of the herpesvirus assembly protein. Herpesvirus proteases have little sequence homology to other known proteases, and all have similar substrate specificity, prefering to cleave Ala-Ser bonds. They exist as a monomer-dimer equilibrium, with the dimer being the active species.
MechansimHerpesvirus protease uses a Ser-His-His catalytic triad. Ser 132 acts as a nucleophile to attack the peptide bond, while His 63 deprotonates the attacking serine residue. The resulting tetrahedral intermediate is stabilised by an oxyanion hole consisting of the backbone NH of Arg 165 and two water molecules positioned by the guanidinium group of Arg 166. Collapse of the tetrahedral intermediate with protonation of the departing amine by His 63 generates an acyl-enzyme intermediate. This is then hydrolysed by a water molecule that is deprotonated by His 63. His 157 functions to modify the pKa of His 63, although its effect of catalysis is much smaller than that of the aspartate in the classical Ser-His-Asp serine proteases.

Catalytic Sites for 1nkk

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
ArgA165165macie:mainChainAmideBackbone NH forms part of oxyanion hole that stabilises the tetrahedral intermediate.
HisA6363macie:sideChainDeprotonates Ser 132 as this residue attacks the peptide bond. Protonates the departing amine leaving group. Later deprotonates a water molecule during hydrolysis of the acyl-enzyme intermediate.
HisA157157macie:sideChainIncreases the pKa of His 63 by forming an additional hydrogen bond to it.
SerA132132macie:sideChainAttacks the peptide carbonyl to form an acyl-enzyme intermediate.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
ArgB465165macie:mainChainAmideBackbone NH forms part of oxyanion hole that stabilises the tetrahedral intermediate.
SerB432132macie:sideChainAttacks the peptide carbonyl to form an acyl-enzyme intermediate.
HisB36363macie:sideChainDeprotonates Ser 132 as this residue attacks the peptide bond. Protonates the departing amine leaving group. Later deprotonates a water molecule during hydrolysis of the acyl-enzyme intermediate.
HisB457157macie:sideChainIncreases the pKa of His 63 by forming an additional hydrogen bond to it.

Annotated By Reference To The Literature - Site 3 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisC1157157macie:sideChainIncreases the pKa of His 63 by forming an additional hydrogen bond to it.
SerC1132132macie:sideChainAttacks the peptide carbonyl to form an acyl-enzyme intermediate.
ArgC1165165macie:mainChainAmideBackbone NH forms part of oxyanion hole that stabilises the tetrahedral intermediate.
HisC106363macie:sideChainDeprotonates Ser 132 as this residue attacks the peptide bond. Protonates the departing amine leaving group. Later deprotonates a water molecule during hydrolysis of the acyl-enzyme intermediate.

Annotated By Reference To The Literature - Site 4 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisD1457157macie:sideChainIncreases the pKa of His 63 by forming an additional hydrogen bond to it.
ArgD1465165macie:mainChainAmideBackbone NH forms part of oxyanion hole that stabilises the tetrahedral intermediate.
HisD136363macie:sideChainDeprotonates Ser 132 as this residue attacks the peptide bond. Protonates the departing amine leaving group. Later deprotonates a water molecule during hydrolysis of the acyl-enzyme intermediate.
SerD1432132macie:sideChainAttacks the peptide carbonyl to form an acyl-enzyme intermediate.

Literature References

Notes:
Welch AR
Herpesvirus proteinase: site-directed mutagenesis used to study maturational, release, and inactivation cleavage sites of precursor and to identify a possible catalytic site serine and histidine.
J Virol 1993 67 7360-7372
PubMed: 8230459
Shieh HS
Three-dimensional structure of human cytomegalovirus protease.
Nature 1996 383 279-282
PubMed: 8805708
Holwerda BC
Activity of two-chain recombinant human cytomegalovirus protease.
J Biol Chem 1994 269 25911-25915
PubMed: 7929296
Khayat R
Structural and biochemical studies of inhibitor binding to human cytomegalovirus protease.
Biochemistry 2003 42 885-891
PubMed: 12549906
Qiu X
Unique fold and active site in cytomegalovirus protease.
Nature 1996 383 275-279
PubMed: 8805707
Khayat R
Investigating the role of histidine 157 in the catalytic activity of human cytomegalovirus protease.
Biochemistry 2001 40 6344-6351
PubMed: 11371196
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