7RH5

Mycobacterial CIII2CIV2 supercomplex, Inhibitor free

Summary for 7RH5

• Entry DOI: 10.2210/pdb7rh5/pdb
• EMDB information: 24455 24456 24457
• Descriptor: Cytochrome c oxidase subunit 1, Cytochrome bc1 complex cytochrome c subunit, LpqE protein, ... (23 entities in total)
• Functional Keywords: electron transport chain, ciii2civ2 supercomplex, membrane protein
• Biological source: Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155); More
• Total number of polymer chains: 24
• Total formula weight: 724115.05

Authors

Di Trani, J.M.,Yanofsky, D.J.,Rubinstein, J.L. (deposition date: 2021-07-16, release date: 2021-08-04, Last modification date: 2021-11-10)

Primary citation

Yanofsky, D.J.,Di Trani, J.M.,Krol, S.,Abdelaziz, R.,Bueler, S.A.,Imming, P.,Brzezinski, P.,Rubinstein, J.L.
Structure of mycobacterial CIII 2 CIV 2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203).
Elife, 10:-, 2021

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 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.

PubMed: 34590581
DOI: 10.7554/eLife.71959

Experimental method

ELECTRON MICROSCOPY (3 Å)