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| | <StructureSection load='5jyp' size='340' side='right'caption='[[5jyp]], [[Resolution|resolution]] 2.74Å' scene=''> | | <StructureSection load='5jyp' size='340' side='right'caption='[[5jyp]], [[Resolution|resolution]] 2.74Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5jyp]] 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=5JYP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JYP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5jyp]] 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=5JYP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JYP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZBS:2-PHENYL-~{N}-[5-[(1~{S},3~{S})-3-[5-(2-PHENYLETHANOYLAMINO)-1,3,4-THIADIAZOL-2-YL]CYCLOHEXYL]-1,3,4-THIADIAZOL-2-YL]ETHANAMIDE'>ZBS</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.74Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5jyo|5jyo]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZBS:2-PHENYL-~{N}-[5-[(1~{S},3~{S})-3-[5-(2-PHENYLETHANOYLAMINO)-1,3,4-THIADIAZOL-2-YL]CYCLOHEXYL]-1,3,4-THIADIAZOL-2-YL]ETHANAMIDE'>ZBS</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=5jyp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jyp OCA], [https://pdbe.org/5jyp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jyp RCSB], [https://www.ebi.ac.uk/pdbsum/5jyp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jyp 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>
| + | |
| - | <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=5jyp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jyp OCA], [http://pdbe.org/5jyp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jyp RCSB], [http://www.ebi.ac.uk/pdbsum/5jyp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jyp 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Glutaminase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ramachandran, S]] | + | [[Category: Ramachandran S]] |
| - | [[Category: Sivaraman, J]] | + | [[Category: Sivaraman J]] |
| - | [[Category: Allosteric inhibition]]
| + | |
| - | [[Category: Gac]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Kga]]
| + | |
| - | [[Category: Warburg effect]]
| + | |
| 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
Cancer cells employ glutaminolysis to provide a source of intermediates for their upregulated biosynthetic needs. Glutaminase, which catalyzes the conversion of glutamine to glutamate, is gaining increasing attention as a potential drug target. Small-molecule inhibitors such as BPTES and CB-839, which target the allosteric site of glutaminase with high specificity, demonstrate immense promise as anti-tumor drugs. Here, we report the study of a new BPTES analog, N,N'-(5,5'-(trans-cyclohexane-1,3-diyl)bis(1,3,4-tiadiazole-5,2-diyl))bis(2-pheny lacetamide) (trans-CBTBP), and compared its inhibitory effect against that of CB-839 and BPTES. We show that CB-839 has a 30- and 50-fold lower IC50 than trans-CBTBP and BPTES, respectively. To explore the structural basis for the differences in their inhibitory efficacy, we solved the complex structures of cKGA with 1S, 3S-CBTBP and CB-839. We found that CB-839 produces a greater degree of interaction with cKGA than 1S, 3S-CBTBP or BPTES. The results of this study will facilitate the rational design of new KGA inhibitors to better treat glutamine-addicted cancers.
Structural basis for exploring the allosteric inhibition of human kidney type glutaminase.,Ramachandran S, Pan CQ, Zimmermann SC, Duvall B, Tsukamoto T, Low BC, Sivaraman J Oncotarget. 2016 Sep 6;7(36):57943-57954. doi: 10.18632/oncotarget.10791. PMID:27462863[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ramachandran S, Pan CQ, Zimmermann SC, Duvall B, Tsukamoto T, Low BC, Sivaraman J. Structural basis for exploring the allosteric inhibition of human kidney type glutaminase. Oncotarget. 2016 Sep 6;7(36):57943-57954. doi: 10.18632/oncotarget.10791. PMID:27462863 doi:http://dx.doi.org/10.18632/oncotarget.10791
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