8S0V

Crystal structure of Cryptosporidium parvum - Trypanosoma cruzi mutant lysyl tRNA synthetase in complex with inhibitor

This is a non-PDB format compatible entry.

Summary for 8S0V

• Entry DOI: 10.2210/pdb8s0v/pdb
• Descriptor: Lysine--tRNA ligase, LYSINE, ~{N}7-cyclopentyl-5,6,8-tris(fluoranyl)-2-methyl-quinazoline-4,7-diamine, ... (7 entities in total)
• Functional Keywords: trna binding, ligase
• Biological source: Cryptosporidium parvum Iowa
• Total number of polymer chains: 2
• Total formula weight: 125020.28

Authors

Dawson, A.,Wyllie, S. (deposition date: 2024-02-14, release date: 2025-03-05, Last modification date: 2025-07-16)

Primary citation

Tulloch, L.B.,Tawell, H.,Taylor, A.E.,Lima, M.L.,Dawson, A.,Carvalho, S.,Wall, R.J.,Corpas-Lopez, V.,Dey, G.,Duggan, J.,Magalhaes, L.G.,Torrie, L.S.,Frame, L.,Robinson, D.,Patterson, S.,Tinti, M.,Weaver, G.W.,Robinson, W.J.,Cal, M.,Kaiser, M.,Maser, P.,Sjo, P.,Perry, B.,Kelly, J.M.,Francisco, A.F.,Bhambra, A.S.,Wyllie, S.
Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease.
Sci Transl Med, 17:eadu4564-eadu4564, 2025

PubMed Abstract: The protozoan parasite causes Chagas disease, which is among the deadliest parasitic infections in Latin America. Current therapies are toxic and lack efficacy against the chronic stage of infection; thus, new drugs are urgently needed. Here, we describe a previously unidentified series of quinazoline compounds with potential against and the related trypanosomatid parasites and . We demonstrated partial efficacy of a lead quinazoline compound in a mouse model of acute Chagas disease. Mechanism of action studies using several orthogonal approaches showed that this quinazoline compound series targeted the ATP-binding pocket of lysyl-tRNA synthetase 1 (KRS1). A high-resolution crystal structure of KRS1 bound to the drug indicated binding interactions that led to KRS1 inhibition. Our study identified KRS1 as a druggable target for treating infection in a mouse model. This quinazoline series shows potential for treating Chagas disease but will require further development to become a future treatment for this neglected disease.

PubMed: 40632837
DOI: 10.1126/scitranslmed.adu4564

Experimental method

X-RAY DIFFRACTION (1.6 Å)