Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)

  1. David J Yanofsky
  2. Justin M Di Trani
  3. Sylwia Krol
  4. Rana Abdelaziz
  5. Stephanie A Bueler
  6. Peter Imming  Is a corresponding author
  7. Peter Brzezinski  Is a corresponding author
  8. John L Rubinstein  Is a corresponding author
  1. The Hospital for Sick Children, Canada
  2. Stockholm University, Sweden
  3. Martin-Luther-Universitaet, Germany
  4. 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

  1. David J Yanofsky

    The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Justin M Di Trani

    The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Sylwia Krol

    Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  4. Rana Abdelaziz

    Pharmaceutical Chemistry, Martin-Luther-Universitaet, Halle (Saale), Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9581-604X
  5. Stephanie A Bueler

    The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Peter Imming

    Martin-Luther-Universitaet, Halle-Wittenberg, Germany
    For correspondence
    peter.imming@pharmazie.uni-halle.de
    Competing interests
    The authors declare that no competing interests exist.
  7. Peter Brzezinski

    Biochemistry and Biophysics, Stockholm university, Stockholm, Sweden
    For correspondence
    peterb@dbb.su.se
    Competing interests
    The authors declare that no competing interests exist.
  8. John L Rubinstein

    The Hospital for Sick Children, Toronto, Canada
    For correspondence
    john.rubinstein@utoronto.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0566-2209

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.

Reviewing Editor

  1. Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom

Publication history

  1. Preprint posted: July 6, 2021 (view preprint)
  2. Received: July 6, 2021
  3. Accepted: September 29, 2021
  4. Accepted Manuscript published: September 30, 2021 (version 1)
  5. Accepted Manuscript updated: October 5, 2021 (version 2)
  6. Version of Record published: October 18, 2021 (version 3)

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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  1. David J Yanofsky
  2. Justin M Di Trani
  3. Sylwia Krol
  4. Rana Abdelaziz
  5. Stephanie A Bueler
  6. Peter Imming
  7. Peter Brzezinski
  8. John L Rubinstein
(2021)
Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)
eLife 10:e71959.
https://doi.org/10.7554/eLife.71959

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