9KUN

Crystal structure of ligand-free trypanosome alternative oxidase

Summary for 9KUN

• Entry DOI: 10.2210/pdb9kun/pdb
• Descriptor: Alternative oxidase, mitochondrial, FE (III) ION, HYDROXIDE ION, ... (5 entities in total)
• Functional Keywords: alternative oxidase, inhibitor, drug, african trypanosomes, oxidoreductase
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 4
• Total formula weight: 126288.14

Authors

Ebiloma, G.U.,Balogun, E.O.,Dardonville, C.,Shiba, T.,De Koning, H.P. (deposition date: 2024-12-04, release date: 2025-09-10)

Primary citation

Ebiloma, G.U.,Balogun, E.O.,Arai, N.,Otani, M.,Baldassarri, C.,Alhejely, A.,Cueto-Diaz, E.,De Koning, H.P.,Dardonville, C.,Shiba, T.
Uncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes.
J.Med.Chem., 68:17155-17174, 2025

PubMed Abstract: The glucose-dependent respiration of bloodstream forms of the parasite depends on an unusual and essential mitochondrial electron-transport system, consisting of glycerol-3-phosphate dehydrogenase and the trypanosome alternative oxidase (TAO). We report here the discovery of an allosteric inhibitor of TAO that displays highly potent activity (EC values in the range 1-20 nM) against the important veterinary pathogens , , , and , i.e., >5-fold greater potency than the standard drugs. The methylene-linked 2-methyl-4-hydroxybenzoate 2-pyridinyldiphenylphosphonium derivative () was the best inhibitor of recombinant TAO (IC = 1.3 nM) via a noncompetitive/allosteric mechanism ( = 3.46 nM). Remarkably, X-ray crystallography showed that was bound to a site of TAO ∼25 Å from the catalytic pocket. Although demonstrated good safety toward mammalian cells (selectivity index >2300), it did not fully clear parasitemia in experimental animals, attributable to a high hepatic clearance.

PubMed: 40464345
DOI: 10.1021/acs.jmedchem.5c00631

Experimental method

X-RAY DIFFRACTION (2.7 Å)