Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates
Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome bcc complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome bcc complex from these pathogenic mycobacteria. Here, w...
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2021
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oai:doaj.org-article:870045ec206547a69bdc59e68d58ae732021-11-25T09:16:07ZStructure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates10.7554/eLife.694182050-084Xe69418https://doaj.org/article/870045ec206547a69bdc59e68d58ae732021-11-01T00:00:00Zhttps://elifesciences.org/articles/69418https://doaj.org/toc/2050-084XPathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome bcc complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome bcc complex from these pathogenic mycobacteria. Here, we report the structures of Mycobacterium tuberculosis cytochrome bcc 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. M. tuberculosis cytochrome bcc 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 QcrBThr313 and QcrBGlu314, residues that are conserved across pathogenic mycobacteria. These high-resolution images provide a basis for the design of new mycobacterial cytochrome bcc inhibitors that could be developed into broad-spectrum drugs to treat mycobacterial infections.Shan ZhouWeiwei WangXiaoting ZhouYuying ZhangYuezheng LaiYanting TangJinxu XuDongmei LiJianping LinXiaolin YangTing RanHongming ChenLuke W GuddatQuan WangYan GaoZihe RaoHongri GongeLife Sciences Publications LtdarticleMycobacterium tuberculosiscytochrome bcc complexcryo-electron microscopyQ203TB47MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021) |
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DOAJ |
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DOAJ |
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EN |
| topic |
Mycobacterium tuberculosis cytochrome bcc complex cryo-electron microscopy Q203 TB47 Medicine R Science Q Biology (General) QH301-705.5 |
| spellingShingle |
Mycobacterium tuberculosis cytochrome bcc complex cryo-electron microscopy Q203 TB47 Medicine R Science Q Biology (General) QH301-705.5 Shan Zhou Weiwei Wang Xiaoting Zhou Yuying Zhang Yuezheng Lai Yanting Tang Jinxu Xu Dongmei Li Jianping Lin Xiaolin Yang Ting Ran Hongming Chen Luke W Guddat Quan Wang Yan Gao Zihe Rao Hongri Gong Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates |
| description |
Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome bcc complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome bcc complex from these pathogenic mycobacteria. Here, we report the structures of Mycobacterium tuberculosis cytochrome bcc 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. M. tuberculosis cytochrome bcc 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 QcrBThr313 and QcrBGlu314, residues that are conserved across pathogenic mycobacteria. These high-resolution images provide a basis for the design of new mycobacterial cytochrome bcc inhibitors that could be developed into broad-spectrum drugs to treat mycobacterial infections. |
| format |
article |
| author |
Shan Zhou Weiwei Wang Xiaoting Zhou Yuying Zhang Yuezheng Lai Yanting Tang Jinxu Xu Dongmei Li Jianping Lin Xiaolin Yang Ting Ran Hongming Chen Luke W Guddat Quan Wang Yan Gao Zihe Rao Hongri Gong |
| author_facet |
Shan Zhou Weiwei Wang Xiaoting Zhou Yuying Zhang Yuezheng Lai Yanting Tang Jinxu Xu Dongmei Li Jianping Lin Xiaolin Yang Ting Ran Hongming Chen Luke W Guddat Quan Wang Yan Gao Zihe Rao Hongri Gong |
| author_sort |
Shan Zhou |
| title |
Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates |
| title_short |
Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates |
| title_full |
Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates |
| title_fullStr |
Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates |
| title_full_unstemmed |
Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates |
| title_sort |
structure of mycobacterium tuberculosis cytochrome bcc in complex with q203 and tb47, two anti-tb drug candidates |
| publisher |
eLife Sciences Publications Ltd |
| publishDate |
2021 |
| url |
https://doaj.org/article/870045ec206547a69bdc59e68d58ae73 |
| work_keys_str_mv |
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1718413569326841856 |