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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 2fqq

E.C. namecaspase-1
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.4.22.36
CSA Homologues of 2fqq
CSA Entries With UniProtID P29466
CSA Entries With EC Number 3.4.22.36
PDBe Entry 2fqq
PDBSum Entry 2fqq
MACiE Entry 2fqq

Literature Report

IntroductionCaspases are thiol endopeptidases that cleave specific proteins after Asp residues and drive apoptosis or inflammation. Caspase-1 is part of the family of inflammatory-caspases, which also includes caspase-4 and caspase-5 in humans and caspase-11, -12, -13 and -14 in mice. Activation of caspase-1 requires oligomerisation of inactive monomeric proenzyme forms.
Caspase-1 has a recognition site of Tyr-Val-Ala-Asp-|-.
MechansimDuring the acylaton step, the carbonyl oxygen of the non-covalently bonded P1 (usually Asp) residue is anchored through hydrogen bonds to the backbone nitrogen atoms of Gly238 and Cys285 which from the oxyanion hole. This increases the polarisation of the C-O bond and therefore facilitates nucleophilic attack of the S atom of Cys285 on the highly electrophilic carbonyl carbon.
The result is a covalent enzyme-substrate adduct - high energy tetrahedral intermediate. The imidazole moiety of His237 acts as a general acid by protonating the alpha-amino group of the leaving peptide product, thus avoiding re-formation of the peptide bond.
Deacylation of the acyl-enzyme complex occurs in a similar way. The deprotonatad His237 side chain abstracts a proton from a water molecule, activating it as a nucleophile to attack the carbonyl carbon of the thioester bond, forming a second tetrahedral intermediate.
Rupture of the S-C bond regenerates the enzyme in a non-covalent complex with the N-terminal peptide product.
Reaction

Catalytic Sites for 2fqq

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
ArgA286286macie:sideChainWorks together with Glu290 to stabilise the transition state intermediate.
AlaA285285macie:sideChainCys285 backbone N forms part of the oxyanion hole which is involved in increasing the electrophicity of the taget carbon. Cys285 also acts as a nucleophile in the acylation step, attacking the electrophilic carbonyl carbon of the substrate.
AlaA285285macie:mainChainAmideCys285 backbone N forms part of the oxyanion hole which is involved in increasing the electrophicity of the taget carbon. Cys285 also acts as a nucleophile in the acylation step, attacking the electrophilic carbonyl carbon of the substrate.
HisA237237macie:sideChainHis237 activates water by proton abstraction to perform nucleophilic attack on the thioester bond of the acyl-enzyme intermediate in the deacylation step. The His237 delta-N atom is also involved in stabilising the leaving group to prevent peptide re-formation.
GlyA238238macie:mainChainAmideThe backbone N of this residue forms part of te oxyanion hole with Cys285.
GluB390390macie:sideChainGlu390 works with Arg286 to stabilise the transition state intermediate together.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
ArgA286286macie:sideChainWorks together with Glu290 to stabilise the transition state intermediate.
AlaA285285macie:sideChainCys285 backbone N forms part of the oxyanion hole which is involved in increasing the electrophicity of the taget carbon. Cys285 also acts as a nucleophile in the acylation step, attacking the electrophilic carbonyl carbon of the substrate.
AlaA285285macie:mainChainAmideCys285 backbone N forms part of the oxyanion hole which is involved in increasing the electrophicity of the taget carbon. Cys285 also acts as a nucleophile in the acylation step, attacking the electrophilic carbonyl carbon of the substrate.
HisA237237macie:sideChainHis237 activates water by proton abstraction to perform nucleophilic attack on the thioester bond of the acyl-enzyme intermediate in the deacylation step. The His237 delta-N atom is also involved in stabilising the leaving group to prevent peptide re-formation.
GlyA238238macie:mainChainAmideThe backbone N of this residue forms part of te oxyanion hole with Cys285.
GluB390390macie:sideChainGlu390 works with Arg286 to stabilise the transition state intermediate together.

Literature References

Notes:
Scheer JM
A common allosteric site and mechanism in caspases.
Proc Natl Acad Sci U S A 2006 103 7595-7600
PubMed: 16682620
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