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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Published in:eLife Vol. 10
Main Authors: Zhou, Shan, Wang, Weiwei, Zhou, Xiaoting, Zhang, Yuying, Lai, Yuezheng, Tang, Yanting, Xu, Jinxu, Li, Dongmei, Lin, Jianping, Yang, Xiaolin, Ran, Ting, Chen, Hongming, Guddat, Luke W, Wang, Quan, Gao, Yan, Rao, Zihe, Gong, Hongri
Format: Journal Article
Language:English
Published: England eLife Sciences Publications Ltd 25.11.2021
eLife Sciences Publications, Ltd
Subjects:
Adenosine triphosphate
Antibiotics
Antitubercular Agents - pharmacology
Bacterial Proteins - chemistry
cryo-electron microscopy
Cryoelectron Microscopy
Cytochrome
cytochrome bcc complex
Cytochromes - chemistry
Data processing
Drug Development
Electron microscopy
Homeostasis
Hydrogen bonding
Hydroquinone
Imidazoles - pharmacology
Infections
Leprosy
Menaquinones
Microscopy
Mycobacterium tuberculosis
Mycobacterium tuberculosis - drug effects
Piperidines - pharmacology
Pyridines - pharmacology
Q203
Quinones
Structural Biology and Molecular Biophysics
TB47
Tuberculosis
Q203
Mycobacterium tuberculosis
cytochrome bcc complex
TB47
structural biology
molecular biophysics
cryo-electron microscopy
ISSN:2050-084X, 2050-084X
Online Access:Get full text
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Summary: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 QcrB Thr 313 and QcrB Glu 314 , 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.
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These authors contributed equally to this work.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.69418