5TQU

Trypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor

Summary for 5TQU

• Entry DOI: 10.2210/pdb5tqu/pdb
• Descriptor: Methionyl-tRNA synthetase, putative, METHIONINE, 2-[2-[[3-(1~{H}-benzimidazol-2-ylamino)propylamino]methyl]-4,6-bis(chloranyl)indol-1-yl]ethanol, ... (6 entities in total)
• Functional Keywords: synthetase, ligase, methionine, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 2
• Total formula weight: 123431.14

Authors

Barros-Alvarez, X.,Hol, W.G.J. (deposition date: 2016-10-24, release date: 2017-04-12, Last modification date: 2023-10-04)

Primary citation

Devine, W.G.,Diaz-Gonzalez, R.,Ceballos-Perez, G.,Rojas, D.,Satoh, T.,Tear, W.,Ranade, R.M.,Barros-Alvarez, X.,Hol, W.G.,Buckner, F.S.,Navarro, M.,Pollastri, M.P.
From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis.
ACS Infect Dis, 3:225-236, 2017

PubMed Abstract: Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure-activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.

PubMed: 28110521
DOI: 10.1021/acsinfecdis.6b00202

Experimental method

X-RAY DIFFRACTION (2.6 Å)