Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)
Autor: | Peter Brzezinski, Sylwia Król, John L. Rubinstein, David J. Yanofsky, Peter Imming, Justin M. Di Trani, Rana Abdelaziz, Stephanie A. Bueler |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Cryo-electron microscopy
QH301-705.5 telacebec (Q203) Science Mycobacterium smegmatis General Biochemistry Genetics and Molecular Biology Mycobacterium tuberculosis 03 medical and health sciences Oxidoreductase Inner membrane structure Biology (General) 030304 developmental biology chemistry.chemical_classification 0303 health sciences General Immunology and Microbiology biology ATP synthase Chemistry General Neuroscience 030302 biochemistry & molecular biology General Medicine biology.organism_classification Electron transport chain cryoEM Structural biology tuberculosis Biophysics biology.protein Medicine respiration |
Zdroj: | eLife, Vol 10 (2021) |
Popis: | The imidazopyridine telacebec, also known as Q203, is one of only a few new classes of compounds in more than 50 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. |
Databáze: | OpenAIRE |
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