Abstract
Cytochromes bd are ubiquitous amongst prokaryotes including many human-pathogenic bacteria. Such complexes are targets for the development of antimicrobial drugs. However, an understanding of the relationship between the structure and functional mechanisms of these oxidases is incomplete. Here, we have determined the 2.8 Å structure of Mycobacterium smegmatis cytochrome bd by single-particle cryo-electron microscopy. This bd oxidase consists of two subunits CydA and CydB, that adopt a pseudo two-fold symmetrical arrangement. The structural topology of its Q-loop domain, whose function is to bind the substrate, quinol, is significantly different compared to the C-terminal region reported for cytochromes bd from Geobacillus thermodenitrificans (G. th) and Escherichia coli (E. coli). In addition, we have identified two potential oxygen access channels in the structure and shown that similar tunnels also exist in G. th and E. coli cytochromes bd. This study provides insights to develop a framework for the rational design of antituberculosis compounds that block the oxygen access channels of this oxidase.
Highlights
Cytochromes bd are ubiquitous amongst prokaryotes including many human-pathogenic bacteria
The heme-copper oxidases (HCO) and bd-type oxidases are two well-known types of membrane-integrated terminal oxidases[1,2]. They catalyze the reduction of molecular oxygen (O2) to water by the respiratory substrate, cytochrome c or quinol, coupled to the generation of a proton motive force utilized for adenosine triphosphate (ATP) synthesis[3,4]
It is likely that these properties of cytochromes bd promote virulence in a number of bacterial pathogens that cause serious infectious diseases to humans, such as Mycobacterium tuberculosis[13], Brucella abortus[14], as well as Salmonella Typhimurium[15,16], Bacteroides[7], and Listeria monocytogenes[17]
Summary
Cytochromes bd are ubiquitous amongst prokaryotes including many human-pathogenic bacteria. Coli[20,21] bd oxidases were observed in the Msm complex, noting that in the G. th and E. coli studies, the genes coding for the associated subunits CydS/X of G. We believe that the Msm bd oxidase contains only two core subunits, CydA and CydB
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