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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1i1i
Original Entry
Title:
Hydrolase
Compound:
Neurolysin
Mutant:
No
UniProt/Swiss-Prot:
P42676-NEUL_RAT
EC Class:
3.4.24.16
Other CSA Entries:
Overview of all sites for 1i1i
Homologues of 1i1i
Entries for UniProt/Swiss-Prot: P42676
Entries for EC: 3.4.24.16
Other Databases:
PDB entry: 1i1i
PDBsum entry: 1i1i
UniProt/Swiss-Prot: P42676
IntEnz entry: 3.4.24.16
Literature Report:
Introduction:
Neurolysin is a zinc metalloprotease which plays a key role in processing ogliopeptides in the nervous system thus degrading peptide hormones and terminating signals. Rat neurolysin shows the classic sequence motif shared by all zinc binding proteases: His-Glu-X-X-His. It also shows structural homology to thermolysin, a well studied member of the class, but little structural identity towards neprilysin despite a similar physiological role.
Mechanism:
The Zinc ion and Glu 503 together activate a water molecule in the active site to act as a nucleophile and attack the substrate peptide. This forms a tetrahedral intermediate, stabilised by the oxyanion hole, made up of the Zinc ion and the OH group of Tyr 613. Subsequent protonation of the leaving group by Glu 503 results in the collapse of the intermediate and the formation of products.
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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLUP 503 526Sidechain
Acid/baseWater
Acts to deprotonate water for nucleophilic attack on the substrate peptide. Subsequently protonates the leaving group to allow collapse of the tetrahedral intermediate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11248043 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 11248043 Current protein Structural similarity to homologue of known mechanism

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
TYRP 613 636Sidechain
ElectrostaticTransition state
Stabilises the tetrahedral intermediate through hydrogen bonding of its OH group with the oxyanion.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11248043 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 11248043 Current protein Structural similarity to homologue of known mechanism

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ZNP 701 0
ElectrostaticTransition state
ElectrostaticWater
Activates water towards nucleophilic attack on the substrate peptide, and subsequently acts to stabilise the tetrahedral intermediate as part of the oxyanion hole.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11248043 Current protein Structural similarity to homologue of known mechanism
PubMed ID 11248043 Current protein Ligand is essential for catalysis
PubMed ID 11248043 Current protein Residue is positioned appropriately (ligand position known)
References:
1
Structure of neurolysin reveals a deep channel that limits substrate access.
C. K. Brown and K. Madauss and W. Lian and M. R. Beck and W. D. Tolbert and D. W. Rodgers
Proc Natl Acad Sci U S A 98, (6) 3127-32, (2001).
11248043
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