PDBsum entry 2qc8

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Ligase PDB id
Protein chains
(+ 4 more) 356 a.a.
ADP ×10
P3S ×10
_MN ×30
_CL ×10
Waters ×231

References listed in PDB file
Key reference
Title Crystal structures of mammalian glutamine synthetases illustrate substrate-Induced conformational changes and provide opportunities for drug and herbicide design.
Authors W.W.Krajewski, R.Collins, L.Holmberg-Schiavone, T.A.Jones, T.Karlberg, S.L.Mowbray.
Ref. J Mol Biol, 2008, 375, 217-228. [DOI no: 10.1016/j.jmb.2007.10.029]
PubMed id 18005987
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.
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.
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