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EC Number

Catalytic Site Atlas

CSA LITERATURE entry for 1qx3

E.C. namecaspase-3
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz)
CSA Homologues of 1qx3There are 100 Homologs
CSA Entries With UniProtID P42574
CSA Entries With EC Number
PDBe Entry 1qx3
PDBSum Entry 1qx3
MACiE Entry 1qx3

Literature Report

IntroductionCaspase-3 from Homo sapiens is a member of a family of intracellular cysteine proteases that cleave substrates specifically at an aspartic acid residue. Caspases share a high degree of homology, not only within caspases from the same species but also across various species. Caspases control the proteolytic cascade central to the initiation and regulation of apoptosis. Caspase-3 is known as the executioner protease. The inactive form of caspase-3 is procaspase-3. This is activated when the procaspase is cleaved at an aspartate residue in the subunit linker, followed by one or more cleavages that remove the pro-domain.
MechansimCys 163 and His 121 are thought to exist as a thiolate/imidazolium ion-pair.
1. Upon binding the substrate, protonated His 121 polarises the carbonyl of the scissile amide bond. This enables Cys 163 to perform nucleophilic attack upon the activated carbonyl carbon. 2. The tetrahedral oxyanion intermediate is stabilised by the protonated His 121 cation and hydrogen bonding to the backbone amide group of Gly 122. A water molecule, held in the correct location through hydrogen bonding to Gly 122 transfers a proton to the amine leaving group. 3. The resulting hydroxy anion performs nucleophilic attack upon the the thioester bond, causing Cys 163 to leave, reforming the thiolate anion.

Catalytic Sites for 1qx3

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisA121121macie:sideChain1. Protonated His 121 deprotonates Cys 163, causing it to become a thiolate. 2. Protonated His 121 stabilises the tetrahedral oxyanion intermediate.
GlyA122122macie:mainChainAmideGly 122 stabilises the tetrahedral transition state through hydrogen bonding with it's backbone amide group.
Gly 122 holds a water molecule in the correct location through hydrogen bonding.This water molecule can donate a proton to the amine leaving group.
CysA163163macie:sideChainCys 163 protonates His 121, causing it to become cationic. Cys 163 performs nucleophilic attack upon the activated carbonyl carbon.

Literature References

Chéreau D
Structural and functional analysis of caspase active sites.
Biochemistry 2003 42 4151-4160
PubMed: 12680769
Brady KD
A catalytic mechanism for caspase-1 and for bimodal inhibition of caspase-1 by activated aspartic ketones.
Bioorg Med Chem 1999 7 621-631
PubMed: 10353641