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Catalytic Site Atlas

CSA LITERATURE entry for 1nmw

E.C. namepeptidylprolyl isomerase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz)
CSA Homologues of 1nmwThere are 28 Homologs
CSA Entries With UniProtID Q13526
CSA Entries With EC Number
PDBe Entry 1nmw
PDBSum Entry 1nmw
MACiE Entry 1nmw

Literature Report

IntroductionProlyl 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.
MechansimThe 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.

Catalytic Sites for 1nmw

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
CysA113113macie:sideChainActs 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.
HisA5959macie:sideChainActs to deprotonate the catalytic nucleophile Cys 113 thus allowing it to form the tetrahedral intermediate.
HisA157157macie:sideChainStabilises the oxyanion transition state through hydrogen bonding between its protonated form and the negative charge on the oxygen.

Literature References

Ranganathan R
Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent.
Cell 1997 89 875-886
PubMed: 9200606