Short talk:
Cryo-EM structure of the actinobacterial respiratory supercomplex: an efficient generator and potential drug target

Wei-Chun Kao1, Carola Hunte1,2

1University of Freiburg, Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, Freiburg im Breisgau, Germany,
2University of Freiburg, Signalling Research Centres BIOSS and CIBSS, Freiburg im Breisgau, Germany

Respiratory chain cytochrome (cyt) bc complexes (complex III) and cyt c oxidases (complex IV) are major generators of the proton motive force that fuels ATP synthesis. They are proposed to assemble into supercomplexes to optimise the energy conversion efficiency, but less is known at the level of atomic detail. Here, we report the 2.8-Å resolution cryo-EM structure of the obligate complex III2-IV2 (cyt bcc-aa3) supercomplex of the actinobacterium Corynebacterium glutamicum [1]. The resolved catalytic position of menaquinol as well as proton channels provide insights in the basis for concerted release of electrons and protons limiting wasteful and deleterious bypass reactions in the cyt bcc complex. A previously unknown menaquinone binding Qc site and a tightly bound lycopene indicate the presence of a built-in free radical handling system. The conformational states of four conserved key protonable groups provide the basis for controlled proton uptake, loading and release and thus for effective proton pumping in cyt c oxidases. Our results show how safe and efficient energy conversion is achieved in a respiratory supercomplex. The well-resolved conformations of inhibitor as well as native substrates in the cryo-EM structure of the supercomplex may aid the rational design of drugs against actinobacteria that cause diphtheria and tuberculosis [2].

[1] W.-C. Kao et al., Structural basis for safe and efficient energy conversion in a respiratory supercomplex, Nat. Commun. 13, 545 (2022)
[2] W.-C. Kao and C. Hunte, Quinone binding sites of cyt bc complexes analysed by x-ray crys- tallography and cryogenic electron microscopy. Biochem. Soc. Trans. 50, 877-893 (2022)


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