First time at Proteopedia? Click on the green links: they change the 3D image. Click and drag the molecules. Proteopedia is a 3D, interactive encyclopedia of proteins, RNA, DNA and other molecules. With a free user account, you can edit pages in Proteopedia. Visit the Main Page to learn more.
|2ojw, resolution 2.05Å ()|
|Ligands:||, , , ,|
|Gene:||GLUL, GLNS (Homo sapiens)|
Crystal structure of human glutamine synthetase in complex with ADP and phosphate
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.
Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design., Krajewski WW, Collins R, Holmberg-Schiavone L, Jones TA, Karlberg T, Mowbray SL, J Mol Biol. 2008 Jan 4;375(1):217-28. Epub 2007 Oct 17. PMID:18005987
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[GLNA_HUMAN] Defects in GLUL are the cause of congenital systemic glutamine deficiency (CSGD) [MIM:610015]. CSGD is a rare developmental disorder with severe brain malformation resulting in multi-organ failure and neonatal death. Glutamine is largely absent from affected patients serum, urine and cerebrospinal fluid.
[GLNA_HUMAN] This enzyme has 2 functions: it catalyzes the production of glutamine and 4-aminobutanoate (gamma-aminobutyric acid, GABA), the latter in a pyridoxal phosphate-independent manner (By similarity). Essential for proliferation of fetal skin fibroblasts.
About this Structure
- Krajewski WW, Collins R, Holmberg-Schiavone L, Jones TA, Karlberg T, Mowbray SL. Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design. J Mol Biol. 2008 Jan 4;375(1):217-28. Epub 2007 Oct 17. PMID:18005987 doi:10.1016/j.jmb.2007.10.029
- ↑ Haberle J, Gorg B, Rutsch F, Schmidt E, Toutain A, Benoist JF, Gelot A, Suc AL, Hohne W, Schliess F, Haussinger D, Koch HG. Congenital glutamine deficiency with glutamine synthetase mutations. N Engl J Med. 2005 Nov 3;353(18):1926-33. PMID:16267323 doi:353/18/1926
- ↑ Vermeulen T, Gorg B, Vogl T, Wolf M, Varga G, Toutain A, Paul R, Schliess F, Haussinger D, Haberle J. Glutamine synthetase is essential for proliferation of fetal skin fibroblasts. Arch Biochem Biophys. 2008 Oct 1;478(1):96-102. doi: 10.1016/j.abb.2008.07.009., Epub 2008 Jul 17. PMID:18662667 doi:10.1016/j.abb.2008.07.009