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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69418 |
| _version_ | 1811227739334639616 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T09:46:43Z |
| format | Article |
| id | doaj.art-870045ec206547a69bdc59e68d58ae73 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:46:43Z |
| publishDate | 2021-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-870045ec206547a69bdc59e68d58ae732022-12-22T03:37:56ZengeLife Sciences Publications LtdeLife2050-084X2021-11-011010.7554/eLife.69418Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidatesShan Zhou0https://orcid.org/0000-0001-5468-3538Weiwei Wang1Xiaoting Zhou2https://orcid.org/0000-0002-8238-8242Yuying Zhang3Yuezheng Lai4Yanting Tang5https://orcid.org/0000-0002-8656-3220Jinxu Xu6Dongmei Li7Jianping Lin8Xiaolin Yang9https://orcid.org/0000-0003-0992-8676Ting Ran10https://orcid.org/0000-0002-1387-4634Hongming Chen11https://orcid.org/0000-0002-8065-8333Luke W Guddat12https://orcid.org/0000-0002-8204-8408Quan Wang13Yan Gao14https://orcid.org/0000-0002-9665-8645Zihe Rao15https://orcid.org/0000-0001-9866-2384Hongri Gong16https://orcid.org/0000-0002-2596-7635State 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, ChinaShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaBioland Laboratory (Guangzhou Regenerative Medicine and Health - Guangdong Laboratory), Guangzhou, ChinaBioland Laboratory (Guangzhou Regenerative Medicine and Health - Guangdong Laboratory), Guangzhou, ChinaSchool of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, AustraliaShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaState 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; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Beijing, China; Laboratory of Structural Biology, Tsinghua University, Beijing, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, ChinaPathogenic 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.https://elifesciences.org/articles/69418Mycobacterium tuberculosiscytochrome bcc complexcryo-electron microscopyQ203TB47 |
| spellingShingle | 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 eLife Mycobacterium tuberculosis cytochrome bcc complex cryo-electron microscopy Q203 TB47 |
| title | 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_short | 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 |
| topic | Mycobacterium tuberculosis cytochrome bcc complex cryo-electron microscopy Q203 TB47 |
| url | https://elifesciences.org/articles/69418 |
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