Get   for     ? 
 Site search     ? 
Catalytic Site Atlas Version 2.2.12
Find Annotated Site: PDB code:
Swiss-Prot code:
EC number:
Help
CSA entry for 1qx3
Original Entry
Title:
Hydrolase
Compound:
Apopain
Mutant:
No
UniProt/Swiss-Prot:
P42574-ICE3_HUMAN
EC Class:
3.4.22.-
Other CSA Entries:
Overview of all sites for 1qx3
Homologues of 1qx3
Entries for UniProt/Swiss-Prot: P42574
Entries for EC: 3.4.22.-
Other Databases:
PDB entry: 1qx3
PDBsum entry: 1qx3
UniProt/Swiss-Prot: P42574
IntEnz entry: 3.4.22.-
Literature Report:
Introduction:
Caspase-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.
Mechanism:
Cys 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.
Sites:

Click to Display Catalytic Site (Get help with this section)
Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 121 121Sidechain
ElectrostaticTransition state
Acid/baseResidue
1. Protonated His 121 deprotonates Cys 163, causing it to become a thiolate. 2. Protonated His 121 stabilises the tetrahedral oxyanion intermediate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 12680769 Current protein Structural similarity to homologue of known mechanism
PubMed ID 12680769 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 12680769 Current protein Computer modelling

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLYA 122 122Backbone amide
ElectrostaticWater
ElectrostaticTransition state
Gly 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.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10353641 Related protein: UniProt P29466 Residue is positioned appropriately (ligand position known)
PubMed ID 12680769 Current protein Computer modelling
PubMed ID 12680769 Current protein Structural similarity to homologue of known mechanism
PubMed ID 10353641 Related protein: UniProt P29466 Structural similarity to homologue of known mechanism
PubMed ID 12680769 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
CYSA 163 163Sidechain
Acid/baseResidue
NucleophileSubstrate
Cys 163 protonates His 121, causing it to become cationic. Cys 163 performs nucleophilic attack upon the activated carbonyl carbon.
Evidence from paper Evidence concerns Evidence type
PubMed ID 12680769 Current protein Structural similarity to homologue of known mechanism
PubMed ID 12680769 Current protein Computer modelling
PubMed ID 12680769 Current protein Residue is positioned appropriately (ligand position known)
References:
1
Structural and functional analysis of caspase active sites.
D. Chéreau and L. Kodandapani and K. J. Tomaselli and A. P. Spada and J. C. Wu
Biochemistry 42, (14) 4151-60, (2003).
12680769
2
A catalytic mechanism for caspase-1 and for bimodal inhibition of caspase-1 by activated aspartic ketones.
K. D. Brady and D. A. Giegel and C. Grinnell and E. Lunney and R. V. Talanian and W. Wong and N. Walker
Bioorg Med Chem 7, (4) 621-31, (1999).
10353641
Which EBI biological databases are available and how do I access them? EBI Site Map