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Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203)
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 82021 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e71959Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2021. Vol. 10, article id e71959
Keywords [en]
Mycobacterium smegmatis, telacebec (Q203), cryoEM, respiration, tuberculosis, structure
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-198837DOI: 10.7554/eLife.71959ISI: 000709344600001PubMedID: 34590581Scopus ID: 2-s2.0-85116880110OAI: oai:DiVA.org:su-198837DiVA, id: diva2:1614438
Available from: 2021-11-25 Created: 2021-11-25 Last updated: 2024-04-04Bibliographically approved
In thesis
1. Respiration in Actinobacteria: Structure, function and inhibition of the III2IV2 supercomplex
Open this publication in new window or tab >>Respiration in Actinobacteria: Structure, function and inhibition of the III2IV2 supercomplex
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The final step of aerobic respiration, oxidative phosphorylation, combines the activities of the electron transport chain and of ATP synthase. The electron transport chain is composed of membrane-bound energy transducers, which are organized in supramolecular assemblies known as respiratory supercomplexes. 

In this work we determined the cryo-EM structure of the obligate III2IV2 supercomplex from the Gram-positive bacterium Corynebacterium glutamicum. The structure shows that the individual complexes are intertwined and that the electron transfer between them occurs via a di-heme cc subunit instead of via soluble cytochrome c. The structure reveals additional features that distinguish the supercomplex from its canonical counterpart. These are a cytoplasmic QcrB loop that occludes the proton-entry point of the complex IV D-pathway, and an FeS cluster in a fixed position. These characteristics are conserved among actinobacteria. 

With the goal to elucidate the structure-function relationship for complexes III and IV in actinobacteria, we also investigated electron and proton transfer kinetics of an obligate respiratory supercomplex from Mycobacterium smegmatis, which is a model organism for Mycobacterium tuberculosis. The results show that the sequence of reactions involved in electron transfer in complex IV is similar to that observed in other A1-type oxidases, but the F to O transition of the catalytic cycle is slower than that reported for canonical complex IV. We also observed that reaction steps previously shown to display pH dependence in canonical complex IV were pH independent in Mycobacterium smegmatis. In addition, proton uptake kinetics through the D-pathway of complex IV were altered with no proton uptake during the F to O step. These findings can be attributed to the presence of the QcrB loop and point towards a possible unique regulatory mechanism for mycobacterial supercomplexes.

As the mycobacterial supercomplex is a promising drug target for tuberculosis treatment, we studied its interaction with the drug candidate Telacebec and the metabolite of an already approved drug, lansoprazole sulfide. We determined the cryo-EM structures of the III2IV2 supercomplex with Telacebec and with lansoprazole sulfide bound in the QP site of the QcrB subunit of complex III. In both structures the inhibitor replaces the natural substrate menaquinol in the inner position of the QP binding pocket and makes multiple interactions with the QcrA and QcrB subunits of complex III. Multiple turnover assays showed that this binding mode inhibits the supercomplex of Mycobacterium smegmatis. Results from our in silico studies show that lansoprazole sulfide is likely to bind to the supercomplex of Mycobacterium tuberculosis in a similar way as was observed for Mycobacterium smegmatis.

 

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm Univeristy, 2024. p. 78
Keywords
bioenergetics, structural biology, electron transport chain, respiratory supercomplex, electron transfer, proton transfer
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-227926 (URN)978-91-8014-747-7 (ISBN)978-91-8014-748-4 (ISBN)
Public defence
2024-05-17, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius Väg 16 B, Stockholm, 09:00 (English)
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Available from: 2024-04-24 Created: 2024-04-04 Last updated: 2024-04-12Bibliographically approved

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Król, SylwiaBrzezinski, Peter

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