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caption="2ojw, resolution 2.05Å" /> | caption="2ojw, resolution 2.05Å" /> | ||
'''Crystal structure of human glutamine synthetase in complex with ADP and phosphate'''<br /> | '''Crystal structure of human glutamine synthetase in complex with ADP and phosphate'''<br /> | ||
== | ==Overview== | ||
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. | |||
==About this Structure== | ==About this Structure== | ||
2OJW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MN, PO4, CL, ADP and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Glutamate--ammonia_ligase Glutamate--ammonia ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.1.2 6.3.1.2] Full crystallographic information is available from [http:// | 2OJW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MN:'>MN</scene>, <scene name='pdbligand=PO4:'>PO4</scene>, <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=ADP:'>ADP</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Glutamate--ammonia_ligase Glutamate--ammonia ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.1.2 6.3.1.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OJW OCA]. | ||
==Reference== | |||
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. 2007 Oct 17;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18005987 18005987] | |||
[[Category: Glutamate--ammonia ligase]] | [[Category: Glutamate--ammonia ligase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| Line 54: | Line 56: | ||
[[Category: synthetase]] | [[Category: synthetase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:31:19 2008'' | ||
Revision as of 12:31, 23 January 2008
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Crystal structure of human glutamine synthetase in complex with ADP and phosphate
OverviewOverview
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.
About this StructureAbout this Structure
2OJW is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as Glutamate--ammonia ligase, with EC number 6.3.1.2 Full crystallographic information is available from OCA.
ReferenceReference
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. 2007 Oct 17;. PMID:18005987
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Glutamate--ammonia ligase
- Homo sapiens
- Single protein
- Arrowsmith, C.
- Berg, S.Van.Den.
- Berglund, H.
- Busam, R.D.
- Collins, R.
- Edwards, A.
- Flodin, S.
- Flores, A.
- Graslund, S.
- Hallberg, B.M.
- Hammarstrom, M.
- Hogbom, M.
- Holmberg-Schiavone, L.
- Johansson, I.
- Karlberg, T.
- Kotenyova, T.
- Moche, M.
- Nilsson, M.E.
- Nordlund, P.
- Nyman, T.
- Ogg, D.
- Persson, C.
- SGC, Structural.Genomics.Consortium.
- Sagemark, J.
- Stenmark, P.
- Sundstrom, M.
- Thorsell, A.G.
- Uppenberg, J.
- Wallden, K.
- Weigelt, J.
- ADP
- CL
- GOL
- MN
- PO4
- Amino-acid biosynthesis
- Ligase
- Sgc
- Structural genomics
- Structural genomics consortium
- Synthetase