spacer
spacer

PDBsum entry 2qc8

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Ligase PDB id
2qc8
Jmol
Contents
Protein chains
(+ 4 more) 356 a.a. *
Ligands
ADP ×10
P3S ×10
Metals
_MN ×30
_CL ×10
Waters ×231
* Residue conservation analysis
PDB id:
2qc8
Name: Ligase
Title: Crystal structure of human glutamine synthetase in complex w and methionine sulfoximine phosphate
Structure: Glutamine synthetase. Chain: a, b, c, d, e, f, g, h, i, j. Synonym: glutamate-ammonia ligase, gs. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: glul, glns. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.60Å     R-factor:   0.168     R-free:   0.217
Authors: T.Karlberg,L.Lehtio,C.H.Arrowsmith,H.Berglund,R.D.Busam,R.Co L.G.Dahlgren,A.Edwards,S.Flodin,A.Flores,S.Graslund,M.Hamma M.Hogbom,I.Johansson,A.Kallas,T.Kotenyova,M.Moche,P.Nordlun T.Nyman,C.Persson,J.Sagemark,M.Sundstrom,A.G.Thorsell,S.Van Berg,J.Weigelt,L.Holmberg-Schiavone,Structural Genomics Con (Sgc)
Key ref:
W.W.Krajewski et al. (2008). Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design. J Mol Biol, 375, 217-228. PubMed id: 18005987 DOI: 10.1016/j.jmb.2007.10.029
Date:
19-Jun-07     Release date:   03-Jul-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P15104  (GLNA_HUMAN) -  Glutamine synthetase
Seq:
Struc:
373 a.a.
356 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: E.C.4.1.1.15  - Glutamate decarboxylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-glutamate = 4-aminobutanoate + CO2
L-glutamate
= 4-aminobutanoate
+ CO(2)
      Cofactor: Pyridoxal 5'-phosphate
Pyridoxal 5'-phosphate
Bound ligand (Het Group name = ADP) matches with 43.33% similarity
   Enzyme class 2: E.C.6.3.1.2  - Glutamate--ammonia ligase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + L-glutamate + NH3 = ADP + phosphate + L-glutamine
ATP
+ L-glutamate
+ NH(3)
=
ADP
Bound ligand (Het Group name = ADP)
corresponds exactly
+ phosphate
+ L-glutamine
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!
  Cellular component     cell body   14 terms 
  Biological process     small molecule metabolic process   16 terms 
  Biochemical function     catalytic activity     12 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.jmb.2007.10.029 J Mol Biol 375:217-228 (2008)
PubMed id: 18005987  
 
 
Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design.
W.W.Krajewski, R.Collins, L.Holmberg-Schiavone, T.A.Jones, T.Karlberg, S.L.Mowbray.
 
  ABSTRACT  
 
Glutamine synthetase (GS) catalyzes the ligation of glutamate and ammonia to form glutamine, with concomitant hydrolysis of ATP. In mammals, the activity eliminates cytotoxic ammonia, at the same time converting neurotoxic glutamate to harmless glutamine; there are a number of links between changes in GS activity and neurodegenerative disorders, such as Alzheimer's disease. In plants, because of its importance in the assimilation and re-assimilation of ammonia, the enzyme is a target of some herbicides. GS is also a central component of bacterial nitrogen metabolism and a potential drug target. Previous studies had investigated the structures of bacterial and plant GSs. In the present publication, we report the first structures of mammalian GSs. The apo form of the canine enzyme was solved by molecular replacement and refined at a resolution of 3 A. Two structures of human glutamine synthetase represent complexes with: a) phosphate, ADP, and manganese, and b) a phosphorylated form of the inhibitor methionine sulfoximine, ADP and manganese; these structures were refined to resolutions of 2.05 A and 2.6 A, respectively. Loop movements near the active site generate more closed forms of the eukaryotic enzymes when substrates are bound; the largest changes are associated with the binding of the nucleotide. Comparisons with earlier structures provide a basis for the design of drugs that are specifically directed at either human or bacterial enzymes. The site of binding the amino acid substrate is highly conserved in bacterial and eukaryotic GSs, whereas the nucleotide binding site varies to a much larger degree. Thus, the latter site offers the best target for specific drug design. Differences between mammalian and plant enzymes are much more subtle, suggesting that herbicides targeting GS must be designed with caution.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Active sites. (a) HsGS active site with bound ADP, MSO-P, and manganese ions. The N-terminal β-grasp domain is in blue, whereas the C-terminal catalytic domain of the adjoining subunit is in gold. Electron density of ligands is shown by using the final SIGMAA-weighted 2m F[o] − d F[c] map contoured at 1 σ (0.26 electrons Å^−3). Conserved hydrophobic residues interacting with the adenine ring of ADP, as described in the text, are shown with ball-and-stick representations. (b) Polar interactions with ligands in the HsGS/MnADP/MSO-P structure.
Figure 5.
Fig. 5. Comparison of active sites of mammalian and mycobacterial GSs. The MtGS/MgADP/MSO-P structure (gray) is superposed on that of HsGS/MnADP/MSO-P (gold), as described in Fig. 4. MSO-P and ADP of HsGS are shown as ball-and-stick models; the HsGS manganese ions are shown as magenta spheres, whereas gray spheres represent the magnesium ions of MtGS. For clarity, only residues of HsGS are labeled.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 375, 217-228) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21353613 J.Häberle, N.Shahbeck, K.Ibrahim, G.F.Hoffmann, and T.Ben-Omran (2011).
Natural course of glutamine synthetase deficiency in a 3 year old patient.
  Mol Genet Metab, 103, 89-91.  
21481771 J.M.van Rooyen, V.R.Abratt, H.Belrhali, and T.Sewell (2011).
Crystal structure of Type III glutamine synthetase: surprising reversal of the inter-ring interface.
  Structure, 19, 471-483.
PDB code: 3o6x
21288152 Y.C.Mao, J.D.Wang, D.Z.Hung, J.F.Deng, and C.C.Yang (2011).
Hyperammonemia following glufosinate-containing herbicide poisoning: a potential marker of severe neurotoxicity.
  Clin Toxicol (Phila), 49, 48-52.  
20237895 G.Estivill, P.Guardado, R.Buser, M.Betti, and A.J.Márquez (2010).
Identification of an essential cysteinyl residue for the structure of glutamine synthetase alpha from Phaseolus vulgaris.
  Planta, 231, 1101-1111.  
20724386 H.Chandra, S.F.Basir, M.Gupta, and N.Banerjee (2010).
Glutamine synthetase encoded by glnA-1 is necessary for cell wall resistance and pathogenicity of Mycobacterium bovis.
  Microbiology, 156, 3669-3677.  
19656298 B.Geissler, A.Bonebrake, K.L.Sheahan, M.E.Walker, and K.J.Satchell (2009).
Genetic determination of essential residues of the Vibrio cholerae actin cross-linking domain reveals functional similarity with glutamine synthetases.
  Mol Microbiol, 73, 858-868.  
19322816 Y.X.He, L.Gui, Y.Z.Liu, Y.Du, Y.Zhou, P.Li, and C.Z.Zhou (2009).
Crystal structure of Saccharomyces cerevisiae glutamine synthetase Gln1 suggests a nanotube-like supramolecular assembly.
  Proteins, 76, 249-254.
PDB code: 3fky
18282486 J.Weigelt, L.D.McBroom-Cerajewski, M.Schapira, Y.Zhao, C.H.Arrowsmith, and C.H.Arrowmsmith (2008).
Structural genomics and drug discovery: all in the family.
  Curr Opin Chem Biol, 12, 32-39.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.