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PDBsum entry 4gg2

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
4gg2
Jmol
Contents
Protein chains
343 a.a.
189 a.a.
Ligands
NAG ×6
GLU
Metals
IOD ×9
_CL
Waters ×444
PDB id:
4gg2
Name: Hydrolase
Title: The crystal structure of glutamate-bound human gamma- glutamyltranspeptidase 1
Structure: Gamma-glutamyltranspeptidase 1 heavy chain. Chain: a. Fragment: unp residues 28-380. Synonym: ggt 1, gamma-glutamyltransferase 1, glutathione hy leukotriene-c4 hydrolase. Engineered: yes. Gamma-glutamyltranspeptidase 1 light chain. Chain: b. Fragment: unp residues 381-569.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ggt, ggt1, hggt1. Expressed in: pichia. Expression_system_taxid: 4919. Expression_system_taxid: 4919
Resolution:
2.21Å     R-factor:   0.142     R-free:   0.183
Authors: M.B.West,Y.Chen,S.Wickham,A.Heroux,K.Cahill,M.H.Hanigan,B.H.
Key ref: M.B.West et al. (2013). Novel insights into eukaryotic γ-glutamyltranspeptidase 1 from the crystal structure of the glutamate-bound human enzyme. J Biol Chem, 288, 31902-31913. PubMed id: 24047895 DOI: 10.1074/jbc.M113.498139
Date:
04-Aug-12     Release date:   25-Sep-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P19440  (GGT1_HUMAN) -  Gamma-glutamyltranspeptidase 1
Seq:
Struc:
 
Seq:
Struc:
569 a.a.
343 a.a.
Protein chain
Pfam   ArchSchema ?
P19440  (GGT1_HUMAN) -  Gamma-glutamyltranspeptidase 1
Seq:
Struc:
 
Seq:
Struc:
569 a.a.
189 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: Chains A, B: E.C.2.3.2.2  - Gamma-glutamyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: A (5-L-glutamyl)-peptide + an amino acid = a peptide + a 5-L-glutamyl amino acid
(5-L-glutamyl)-peptide
+
amino acid
Bound ligand (Het Group name = GLU)
matches with 83.33% similarity
= peptide
+
5-L-glutamyl amino acid
Bound ligand (Het Group name = NAG)
matches with 45.00% similarity
   Enzyme class 3: Chains A, B: E.C.3.4.19.13  - Glutathione hydrolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Glutathione + H2O = L-cysteinylglycine + L-glutamate
Glutathione
+ H(2)O
= L-cysteinylglycine
+
L-glutamate
Bound ligand (Het Group name = GLU)
matches with 50.00% similarity
   Enzyme class 4: Chains A, B: E.C.3.4.19.14  - Leukotriene-C(4) hydrolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Leukotriene C4 + H2O = leukotriene D4 + L-glutamate
Leukotriene C(4)
+ H(2)O
= leukotriene D(4)
+
L-glutamate
Bound ligand (Het Group name = GLU)
matches with 50.00% similarity
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     glutathione metabolic process   1 term 
  Biochemical function     gamma-glutamyltransferase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M113.498139 J Biol Chem 288:31902-31913 (2013)
PubMed id: 24047895  
 
 
Novel insights into eukaryotic γ-glutamyltranspeptidase 1 from the crystal structure of the glutamate-bound human enzyme.
M.B.West, Y.Chen, S.Wickham, A.Heroux, K.Cahill, M.H.Hanigan, B.H.Mooers.
 
  ABSTRACT  
 
The enzyme γ-glutamyltranspeptidase 1 (GGT1) is a conserved member of the N-terminal nucleophile hydrolase family that cleaves the γ-glutamyl bond of glutathione and other γ-glutamyl compounds. In animals, GGT1 is expressed on the surface of the cell and has critical roles in maintaining cysteine levels in the body and regulating intracellular redox status. Expression of GGT1 has been implicated as a potentiator of asthma, cardiovascular disease, and cancer. The rational design of effective inhibitors of human GGT1 (hGGT1) has been delayed by the lack of a reliable structural model. The available crystal structures of several bacterial GGTs have been of limited use due to differences in the catalytic behavior of bacterial and mammalian GGTs. We report the high resolution (1.67 Å) crystal structure of glutamate-bound hGGT1, the first of any eukaryotic GGT. Comparisons of the active site architecture of hGGT1 with those of its bacterial orthologs highlight key differences in the residues responsible for substrate binding, including a bimodal switch in the orientation of the catalytic nucleophile (Thr-381) that is unique to the human enzyme. Compared with several bacterial counterparts, the lid loop in the crystal structure of hGGT1 adopts an open conformation that allows greater access to the active site. The hGGT1 structure also revealed tightly bound chlorides near the catalytic residue that may contribute to catalytic activity. These are absent in the bacterial GGTs. These differences between bacterial and mammalian GGTs and the new structural data will accelerate the development of new therapies for GGT1-dependent diseases.
 

 

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