8GCC

T. cruzi topoisomerase II alpha bound to dsDNA and the covalent inhibitor CT1

8GCC の概要

• エントリーDOI: 10.2210/pdb8gcc/pdb
• EMDBエントリー: 29930
• 分子名称: 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)
• 機能のキーワード: topoisomerase, dna binding protein, topoisomerase inhibitor, isomerase
• 由来する生物種: Trypanosoma cruzi strain CL Brener; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 196650.69

構造登録者

Schenk, A.,Deniston, C.,Noeske, J. (登録日: 2023-03-01, 公開日: 2023-07-12, 最終更新日: 2024-11-06)

主引用文献

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

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: 37384702
DOI: 10.1126/science.adh0614

実験手法

ELECTRON MICROSCOPY (2.94 Å)