6qu4

Crystal Structure of Phosphofructokinase from Trypanosoma brucei in complex with an allosteric inhibitor ctcb405

spinqualitylabelsall models 6qu4, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6qu4 is a 4 chain structure with sequence from Trypanosoma brucei brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.75Å Ligands: CIT, GOL, JJ2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphofructokinase 3D structures

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