Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)
- The Hospital for Sick Children, Canada
- Stockholm University, Sweden
- Martin-Luther-Universitaet, Germany
- Stockholm university, Sweden
Abstract
The imidazopyridine telacebec, also known as Q203, is one of only a few new classes of compounds in more than fifty years with demonstrated antituberculosis activity in humans. Telacebec inhibits the mycobacterial respiratory supercomplex composed of complexes III and IV (CIII2CIV2). In mycobacterial electron transport chains, CIII2CIV2 replaces canonical CIII and CIV, transferring electrons from the intermediate carrier menaquinol to the final acceptor, molecular oxygen, while simultaneously transferring protons across the inner membrane to power ATP synthesis. We show that telacebec inhibits the menaquinol:oxygen oxidoreductase activity of purified Mycobacterium smegmatis CIII2CIV2 at concentrations similar to those needed to inhibit electron transfer in mycobacterial membranes and Mycobacterium tuberculosis growth in culture. We then used electron cryomicroscopy (cryoEM) to determine structures of CIII2CIV2 both in the presence and absence of telacebec. The structures suggest that telacebec prevents menaquinol oxidation by blocking two different menaquinol binding modes to prevent CIII2CIV2 activity.
Data availability
Data deposition: all electron cryomicroscopy maps described in this article have been deposited in the Electron Microscopy Data Bank (EMDB) (accession numbers EMD-24455 to EMD-24457) and atomic models have been deposited in the Protein Database (PDB) (accession numbers 7RH5 to 7RH7).
Article and author information
Author details
Funding
Canadian Institutes of Health Research (PJT162186)
- John L Rubinstein
The Alice and Knut Wallenberg Foundation (2019.0043)
- Peter Brzezinski
Swedish Research Council (2018-04619)
- Peter Brzezinski
Canadian Institutes of Health Research (PGS-M)
- David J Yanofsky
Canadian Institutes of Health Research (PDF)
- Justin M Di Trani
Canada Research Chairs
- John L Rubinstein
Canada Foundation for Innovation
- John L Rubinstein
Ontario Research Foundation
- John L Rubinstein
University of Toronto
- David J Yanofsky
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Yanofsky et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)
eLife 10:e71959.
https://doi.org/10.7554/eLife.71959
