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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1nmw
Original Entry
Title:
Isomerase
Compound:
Peptidyl-prolyl cis-trans isomerase nima- interacting 1
Mutant:
No
UniProt/Swiss-Prot:
Q13526-PIN1_HUMAN
EC Class:
5.2.1.8
Other CSA Entries:
Overview of all sites for 1nmw
Homologues of 1nmw
Entries for UniProt/Swiss-Prot: Q13526
Entries for EC: 5.2.1.8
Other Databases:
PDB entry: 1nmw
PDBsum entry: 1nmw
UniProt/Swiss-Prot: Q13526
IntEnz entry: 5.2.1.8
Literature Report:
Introduction:
Prolyl isomerase is able to convert the cis and trans forms of peptide bonds involving proline. This alters the 3d structure of the target proteins, which activates them or deactivates them so that they can take part in signal pathways inside the cell. The human prolyl isomerase hPin1 targets many important proteins after they have been phosphorylated by ser/thr kinases, being involved specifically in G2/M transitions in the cell cycle. As a result, mutations to the protein have been implicated in many forms of cancer.
Mechanism:
The cis and trans forms of the prolyl peptide bond are, unlike peptide bonds involving other amino acids, very similar in energy levels. However, interconversion involves breaking the resonance overlap of the CN partial double bond, with very high activation energy. The enzyme is able to reduce this activation barrier by the formation of a tetrahedral intermediate: Cys 113, deprotonated by His 57, attacks the carbonyl of the peptide bond to form an oxyanion intermediate stabilised by His 157. As the tetrahedral intermediate does not have partial double bond character, rotation around the CN bond can occur easily. Collapse of the tetrahedral intermediate then occurs with Cys 113 protonated by His 57 to allow it to act as a leaving group.
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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 59 59Sidechain
Acid/baseResidue
Acts to deprotonate the catalytic nucleophile Cys 113 thus allowing it to form the tetrahedral intermediate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 9200606 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 9200606 Current protein pH dependence of reaction

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
CYSA 113 113Sidechain
NucleophileSubstrate
Acts as nucleophile to attack the carbonyl moiety of the prolyl peptide bond leading to a tetrahedral intermediate which then collapses to form the cis/trans product.
Evidence from paper Evidence concerns Evidence type
PubMed ID 9200606 Current protein Mutagenesis of residue
PubMed ID 9200606 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 157 157Sidechain
ElectrostaticTransition state
Stabilises the oxyanion transition state through hydrogen bonding between its protonated form and the negative charge on the oxygen.
Evidence from paper Evidence concerns Evidence type
PubMed ID 9200606 Current protein pH dependence of reaction
PubMed ID 9200606 Current protein Residue is positioned appropriately (ligand position known)
References:
1
Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent.
R. Ranganathan and K. P. Lu and T. Hunter and J. P. Noel
Cell 89, (6) 875-86, (1997).
9200606
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