6QU3

Crystal Structure of Phosphofructokinase from Trypanosoma brucei in complex with an allosteric inhibitor ctcb360

Summary for 6QU3

• Entry DOI: 10.2210/pdb6qu3/pdb
• Related: 2hig 3f5m
• Descriptor: ATP-dependent 6-phosphofructokinase, 1-[(3,4-dichlorophenyl)methyl]-7~{H}-pyrrolo[3,2-c]pyridin-4-one, CITRIC ACID, ... (6 entities in total)
• Functional Keywords: glycolysis, inhibitor, allostery, transferase
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 4
• Total formula weight: 225553.36

Authors

McNae, I.W.,Dornan, J.,Walkinshaw, M.D. (deposition date: 2019-02-26, release date: 2020-03-18, Last modification date: 2024-01-24)

Primary citation

McNae, I.W.,Kinkead, J.,Malik, D.,Yen, L.H.,Walker, M.K.,Swain, C.,Webster, S.P.,Gray, N.,Fernandes, P.M.,Myburgh, E.,Blackburn, E.A.,Ritchie, R.,Austin, C.,Wear, M.A.,Highton, A.J.,Keats, A.J.,Vong, A.,Dornan, J.,Mottram, J.C.,Michels, P.A.M.,Pettit, S.,Walkinshaw, M.D.
Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice.
Nat Commun, 12:1052-1052, 2021

PubMed Abstract: 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.

PubMed: 33594070
DOI: 10.1038/s41467-021-21273-6

Experimental method

X-RAY DIFFRACTION (2.35 Å)