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| | ==Crystal structure of human glutaminase in complex DON== | | ==Crystal structure of human glutaminase in complex DON== |
| - | <StructureSection load='4o7d' size='340' side='right' caption='[[4o7d]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='4o7d' size='340' side='right'caption='[[4o7d]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4o7d]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O7D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4O7D FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4o7d]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O7D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4O7D FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ONL:5-OXO-L-NORLEUCINE'>ONL</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ONL:5-OXO-L-NORLEUCINE'>ONL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GLS, GLS1, KIAA0838 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4o7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o7d OCA], [https://pdbe.org/4o7d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4o7d RCSB], [https://www.ebi.ac.uk/pdbsum/4o7d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4o7d ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glutaminase Glutaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.2 3.5.1.2] </span></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4o7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o7d OCA], [http://pdbe.org/4o7d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4o7d RCSB], [http://www.ebi.ac.uk/pdbsum/4o7d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4o7d ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GLSK_HUMAN GLSK_HUMAN]] Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate in the brain. Isoform 2 lacks catalytic activity. | + | [https://www.uniprot.org/uniprot/GLSK_HUMAN GLSK_HUMAN] Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate in the brain. Isoform 2 lacks catalytic activity. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Glutaminase|Glutaminase]] | + | *[[Glutaminase 3D structures|Glutaminase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Glutaminase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Sivaraman, J]] | + | [[Category: Sivaraman J]] |
| - | [[Category: Thangavelu, K]] | + | [[Category: Thangavelu K]] |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
Function
GLSK_HUMAN Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate in the brain. Isoform 2 lacks catalytic activity.
Publication Abstract from PubMed
Glutaminase is a metabolic enzyme responsible for glutaminolysis, a process harnessed by cancer cells to feed their accelerated growth and proliferation. Among the glutaminase isoforms, human kidney-type glutaminase (KGA) is often upregulated in cancer and is thus touted as an attractive drug target. Here we report the active site inhibition mechanism of KGA through the crystal structure of the catalytic domain of KGA (cKGA) in complex with 6-diazo-5-oxo-L-norleucine (DON), a substrate analogue of glutamine. DON covalently binds with the active site Ser286 and interacts with residues such as Tyr249, Asn335, Glu381, Asn388, Tyr414, Tyr466 and Val484. The nucleophilic attack of Ser286 sidechain on DON releases the diazo group (N2) from the inhibitor and results in the formation of an enzyme-inhibitor complex. Mutational studies confirmed the key role of these residues in the activity of KGA. This study will be important in the development of KGA active site inhibitors for therapeutic interventions.
Structural basis for the active site inhibition mechanism of human kidney-type glutaminase (KGA).,Thangavelu K, Chong QY, Low BC, Sivaraman J Sci Rep. 2014 Jan 23;4:3827. doi: 10.1038/srep03827. PMID:24451979[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Thangavelu K, Chong QY, Low BC, Sivaraman J. Structural basis for the active site inhibition mechanism of human kidney-type glutaminase (KGA). Sci Rep. 2014 Jan 23;4:3827. doi: 10.1038/srep03827. PMID:24451979 doi:http://dx.doi.org/10.1038/srep03827
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