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-Structure paper
Title | Structure of mycobacterial CIIICIV respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203). |
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Journal, issue, pages | Elife, Vol. 10, Year 2021 |
Publish date | Sep 30, 2021 |
Authors | David J Yanofsky / Justin M Di Trani / Sylwia Król / Rana Abdelaziz / Stephanie A Bueler / Peter Imming / Peter Brzezinski / John L Rubinstein / |
PubMed Abstract | 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 ...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 (CIIICIV). In mycobacterial electron transport chains, CIIICIV 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 CIIICIV at concentrations similar to those needed to inhibit electron transfer in mycobacterial membranes and growth in culture. We then used electron cryomicroscopy (cryoEM) to determine structures of CIIICIV 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 CIIICIV activity. |
External links | Elife / PubMed:34590581 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.0 - 3.5 Å |
Structure data | EMDB-24455, PDB-7rh5: EMDB-24456, PDB-7rh6: EMDB-24457, PDB-7rh7: |
Chemicals | ChemComp-CU: ChemComp-HEA: ChemComp-CDL: ChemComp-HEM: ChemComp-MQ9: ChemComp-9Y0: ChemComp-PLM: ChemComp-9XX: ChemComp-HEC: ChemComp-9YF: ChemComp-FES: ChemComp-HUU: |
Source |
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Keywords | MEMBRANE PROTEIN / Electron transport chain / CIII2CIV2 supercomplex |