Quinone binding sites of cyt bc complexes analysed by X-ray crystallography and cryogenic electron microscopy

Cytochrome (cyt) bc(1), bcc and b(6)f complexes, collectively referred to as cyt bc complexes, are homologous isoprenoid quinol oxidising enzymes present in diverse phylogenetic lineages. Cyt bc(1) and bcc complexes are constituents of the electron transport chain (ETC) of cellular respiration, and cyt b(6)f complex is a component of the photosynthetic ETC. Cyt bc complexes share in general the same Mitchellian Q cycle mechanism, with which they accomplish proton translocation and thus contribute to the generation of proton motive force which drives ATP synthesis. They therefore require a quinol oxidation (Q(o)) and a quinone reduction (Q(i)) site. Yet, cyt bc complexes evolved to adapt to specific electrochemical properties of different quinone species and exhibit structural diversity. This review summarises structural information on native quinones and quinone-like inhibitors bound in cyt bc complexes resolved by X-ray crystallography and cryo-EM structures. Although the Q(i) site architecture of cyt bc(1) complex and cyt bcc complex differs considerably, quinone molecules were resolved at the respective Q(i) sites in very similar distance to haem b(H). In contrast, more diverse positions of native quinone molecules were resolved at Q(o) sites, suggesting multiple quinone binding positions or captured snapshots of trajectories toward the catalytic site. A wide spectrum of inhibitors resolved at Q(o) or Q(i) site covers fungicides, antimalarial and antituberculosis medications and drug candidates. The impact of these structures for characterising the Q cycle mechanism, as well as their relevance for the development of medications and agrochemicals are discussed.