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| | <StructureSection load='6qu5' size='340' side='right'caption='[[6qu5]], [[Resolution|resolution]] 3.40Å' scene=''> | | <StructureSection load='6qu5' size='340' side='right'caption='[[6qu5]], [[Resolution|resolution]] 3.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6qu5]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Trybb Trybb]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QU5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QU5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6qu5]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei Trypanosoma brucei brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QU5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QU5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JJ8:1-[(3,4-dichlorophenyl)methyl]imidazole'>JJ8</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]] 3.4Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pfk ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5702 TRYBB])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JJ8:1-[(3,4-dichlorophenyl)methyl]imidazole'>JJ8</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/6-phosphofructokinase 6-phosphofructokinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.11 2.7.1.11] </span></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=6qu5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qu5 OCA], [https://pdbe.org/6qu5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qu5 RCSB], [https://www.ebi.ac.uk/pdbsum/6qu5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qu5 ProSAT]</span></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=6qu5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qu5 OCA], [https://pdbe.org/6qu5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qu5 RCSB], [https://www.ebi.ac.uk/pdbsum/6qu5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qu5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/PFKA_TRYBB PFKA_TRYBB]] Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.[HAMAP-Rule:MF_03186]
| + | [https://www.uniprot.org/uniprot/PFKA_TRYBB PFKA_TRYBB] Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.[HAMAP-Rule:MF_03186] |
| | <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: 6-phosphofructokinase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Trybb]] | + | [[Category: Trypanosoma brucei brucei]] |
| - | [[Category: Dornan, J]] | + | [[Category: Dornan J]] |
| - | [[Category: McNae, I W]] | + | [[Category: McNae IW]] |
| - | [[Category: Walkinshaw, M D]] | + | [[Category: Walkinshaw MD]] |
| - | [[Category: Allostery]]
| + | |
| - | [[Category: Glycolysis]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
PFKA_TRYBB Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.[HAMAP-Rule:MF_03186]
Publication Abstract from PubMed
The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.
Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice.,McNae IW, Kinkead J, Malik D, Yen LH, Walker MK, Swain C, Webster SP, Gray N, Fernandes PM, Myburgh E, Blackburn EA, Ritchie R, Austin C, Wear MA, Highton AJ, Keats AJ, Vong A, Dornan J, Mottram JC, Michels PAM, Pettit S, Walkinshaw MD Nat Commun. 2021 Feb 16;12(1):1052. doi: 10.1038/s41467-021-21273-6. PMID:33594070[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ McNae IW, Kinkead J, Malik D, Yen LH, Walker MK, Swain C, Webster SP, Gray N, Fernandes PM, Myburgh E, Blackburn EA, Ritchie R, Austin C, Wear MA, Highton AJ, Keats AJ, Vong A, Dornan J, Mottram JC, Michels PAM, Pettit S, Walkinshaw MD. Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice. Nat Commun. 2021 Feb 16;12(1):1052. doi: 10.1038/s41467-021-21273-6. PMID:33594070 doi:http://dx.doi.org/10.1038/s41467-021-21273-6
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