State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, China.
State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
Elife. 2021 Nov 25;10:e69418. doi: 10.7554/eLife.69418.
Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome complex from these pathogenic mycobacteria. Here, we report the structures of cytochrome alone (2.68 Å resolution) and in complex with clinical drug candidates Q203 (2.67 Å resolution) and TB47 (2.93 Å resolution) determined by single-particle cryo-electron microscopy. cytochrome forms a dimeric assembly with endogenous menaquinone/menaquinol bound at the quinone/quinol-binding pockets. We observe Q203 and TB47 bound at the quinol-binding site and stabilized by hydrogen bonds with the side chains of Thr and Glu, residues that are conserved across pathogenic mycobacteria. These high-resolution images provide a basis for the design of new mycobacterial cytochrome inhibitors that could be developed into broad-spectrum drugs to treat mycobacterial infections.
致病分枝杆菌对全球人类健康构成持续威胁。最近，细胞色素 c 复合物作为抗生素药物开发的靶点引起了关注。然而，目前尚无这些致病分枝杆菌的细胞色素 c 复合物的结构信息。在这里，我们通过单颗粒冷冻电子显微镜报告了细胞色素 c 单独（2.68 Å 分辨率）和与临床药物候选物 Q203（2.67 Å 分辨率）和 TB47（2.93 Å 分辨率）复合物的结构。细胞色素 c 形成二聚体组装，内源性menaquinone/menaquinol 结合在醌/氢醌结合口袋中。我们观察到 Q203 和 TB47 结合在氢醌结合位点，并通过与 Thr 和 Glu 侧链的氢键稳定，这些残基在致病分枝杆菌中是保守的。这些高分辨率图像为设计新的分枝杆菌细胞色素 c 抑制剂提供了基础，这些抑制剂可以开发成广谱药物来治疗分枝杆菌感染。
