6QU5

Crystal Structure of Phosphofructokinase from Trypanosoma brucei in complex with an allosteric inhibitor ctcb12

6QU5 の概要

• エントリーDOI: 10.2210/pdb6qu5/pdb
• 分子名称: ATP-dependent 6-phosphofructokinase, CITRIC ACID, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: glycolysis, inhibitor, allostery, transferase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 448293.02

構造登録者

McNae, I.W.,Dornan, J.,Walkinshaw, M.D. (登録日: 2019-02-26, 公開日: 2020-03-18, 最終更新日: 2025-10-01)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.4 Å)