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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 1qtn

E.C. namecaspase-8
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.4.22.61
CSA Homologues of 1qtn1f9e,1i4e,1jxq,1nw9,1qdu,2c2z,2fun,2k7z,3h11,
CSA Entries With UniProtID Q14790
CSA Entries With EC Number 3.4.22.61
PDBe Entry 1qtn
PDBSum Entry 1qtn
MACiE Entry 1qtn

Literature Report

IntroductionCaspase-8 from Homo sapiens is a cysteine dependent, aspartate specific protease. When activated, it will cleave peptide bonds of other downstream caspases in order to activate them. Caspase-8 must be activated in order to become a protease. It is involved in the process of apoptosis (programmed cell death) which is a central role in the development and homeostasis of an organism.
Mechansim1. The backbone NH of Gly 350 forms the oxyanion hole, and activates the scissile carbonyl bond for nucleophilic attack. 2. His 317 is made more basic through hydrogen bonding with the oxygen atom from the backbone carbonyl of Arg 258. 3. His 317 deprotonates the Cys 360 side chain, activating it so the S atom nucleophilically attacks the carbonyl of the scissile peptide bond, forming a negatively charged, tetrahedral intermediate. 4. The intermediate is stabilised by hydrogen bonding to the backbone NH of Gly 350. 5. The carbonyl is reformed, and the leaving group amine is protonated by the previously protonated His 317. 6. His 317 then activates a water molecule for nucleophilic attack on the carbonyl by deprotonating it. 7. The negatively charged, tetrahedral intermediate is again stabilised by hydrogen bonding to the backbone NH of Gly 350. 8. The carbonyl is again reformed, and the protonated His 317 donates a proton to the leaving group Cys 360.
Reaction

Catalytic Sites for 1qtn

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GlyA350350macie:mainChainAmideThe backbone NH of Gly 350 hydrogen bonds to the carbonyl oxygen of the scissile peptide bond. This activates it for nucleophilic attack, and also helps to stabilise the negatively charged, tetrahedral intermediate.
HisA317317macie:sideChainHis 317 deprotonates Cys 360, which then goes on to nucleophilically attack the substrate. The protonated form of His 317 then donates a proton to the leaving group amine as the carbonyl is reformed. His 317 then deprotonates a water molecule which goes on to nucleophilically attack the carbonyl. Protonated His 317 then donates a proton back to the leaving group Cys 360 as the carbonyl is once more reformed.
CysA360360macie:sideChainThe side chain SH of Cys 360 is deprotonated by His 317, and nucleophilically attacks the carbonyl of the scissile bond, forming a negatively charged, tetrahedral intermediate.
ArgA258258macie:mainChainCarbonylThe carbonyl oxygen of Arg 258 acts electrostatically on His 317, making it more basic, and thereby making it more ready to accept a proton from Cys 360.

Literature References

Notes:
Watt W
The atomic-resolution structure of human caspase-8, a key activator of apoptosis.
Structure 1999 7 1135-1143
PubMed: 10508785
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