8GCC
T. cruzi topoisomerase II alpha bound to dsDNA and the covalent inhibitor CT1
Summary for 8GCC
| Entry DOI | 10.2210/pdb8gcc/pdb |
| EMDB information | 29930 |
| Descriptor | DNA topoisomerase 2, DNA (28-MER), 2-{3-[(Z)-iminomethyl]-1H-1,2,4-triazol-1-yl}-1-{(3M)-3-[2-(trifluoromethyl)phenyl]-6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one (3 entities in total) |
| Functional Keywords | topoisomerase, dna binding protein, topoisomerase inhibitor, isomerase |
| Biological source | Trypanosoma cruzi strain CL Brener More |
| Total number of polymer chains | 4 |
| Total formula weight | 196650.69 |
| Authors | Schenk, A.,Deniston, C.,Noeske, J. (deposition date: 2023-03-01, release date: 2023-07-12, Last modification date: 2024-11-06) |
| Primary citation | Rao, S.P.S.,Gould, M.K.,Noeske, J.,Saldivia, M.,Jumani, R.S.,Ng, P.S.,Rene, O.,Chen, Y.L.,Kaiser, M.,Ritchie, R.,Francisco, A.F.,Johnson, N.,Patra, D.,Cheung, H.,Deniston, C.,Schenk, A.D.,Cortopassi, W.A.,Schmidt, R.S.,Wiedemar, N.,Thomas, B.,Palkar, R.,Ghafar, N.A.,Manoharan, V.,Luu, C.,Gable, J.E.,Wan, K.F.,Myburgh, E.,Mottram, J.C.,Barnes, W.,Walker, J.,Wartchow, C.,Aziz, N.,Osborne, C.,Wagner, J.,Sarko, C.,Kelly, J.M.,Manjunatha, U.H.,Maeser, P.,Jiricek, J.,Lakshminarayana, S.B.,Barrett, M.P.,Diagana, T.T. Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections. Science, 380:1349-1356, 2023 Cited by PubMed Abstract: Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease. PubMed: 37384702DOI: 10.1126/science.adh0614 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.94 Å) |
Structure validation
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