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Structure of mycobacterial ATP synthase with the TB drug bedaquiline

View ORCID ProfileHui Guo, View ORCID ProfileGautier M. Courbon, Stephanie A. Bueler, View ORCID ProfileJuntao Mai, View ORCID ProfileJun Liu, View ORCID ProfileJohn L. Rubinstein
doi: https://doi.org/10.1101/2020.08.06.225375
Hui Guo
1Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
2Department of Medical Biophysics, The University of Toronto, Ontario, Canada
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Gautier M. Courbon
1Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
2Department of Medical Biophysics, The University of Toronto, Ontario, Canada
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Stephanie A. Bueler
1Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
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Juntao Mai
3Department of Molecular Genetics, The University of Toronto, Ontario, Canada
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Jun Liu
3Department of Molecular Genetics, The University of Toronto, Ontario, Canada
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John L. Rubinstein
1Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
2Department of Medical Biophysics, The University of Toronto, Ontario, Canada
3Department of Molecular Genetics, The University of Toronto, Ontario, Canada
4Department of Biochemistry, The University of Toronto, Ontario, Canada
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  • For correspondence: john.rubinstein@utoronto.ca
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Summary

Tuberculosis (TB), the leading cause of death by infectious disease worldwide, is increasingly resistant to first line antibiotics. Developed from a screen against Mycobacterium smegmatis, bedaquiline can sterilize even latent M. tuberculosis infections that may otherwise persist for decades and has become a cornerstone of treatment for multidrug resistant and extensively-drug resistant TB. Bedaquiline targets mycobacterial ATP synthase, an essential enzyme in the obligate aerobic Mycobacterium genus. However, how the drug binds the intact enzyme is unknown. We determined the structure of M. smegmatis ATP synthase with and without bedaquiline. The drug-free structure reveals hook-like extensions from the enzyme’s α subunits that inhibit ATP hydrolysis in low-energy conditions, such as during latent infections. Bedaquiline binding induces global conformational changes in ATP synthase, creating tight binding pockets at the interface of subunits a and c. These binding sites explain the drug’s structure-activity relationship and its potency as an antibiotic for TB.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 06, 2020.
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Structure of mycobacterial ATP synthase with the TB drug bedaquiline
Hui Guo, Gautier M. Courbon, Stephanie A. Bueler, Juntao Mai, Jun Liu, John L. Rubinstein
bioRxiv 2020.08.06.225375; doi: https://doi.org/10.1101/2020.08.06.225375
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Structure of mycobacterial ATP synthase with the TB drug bedaquiline
Hui Guo, Gautier M. Courbon, Stephanie A. Bueler, Juntao Mai, Jun Liu, John L. Rubinstein
bioRxiv 2020.08.06.225375; doi: https://doi.org/10.1101/2020.08.06.225375

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