The long Q‐loop of <i>Escherichia coli</i> cytochrome <i>bd</i> oxidase is required for assembly and structural integrity

Thesseling, Alexander; Burschel, Sabrina; Wohlwend, Daniel; Friedrich, Thorsten

doi:10.1002/1873-3468.13749

Cited by 19 publications

(21 citation statements)

References 27 publications

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“…Members of the L-subfamily exhibit a C-terminal insertion in their Q-loop which adopts a helix-turn-helix fold located at the periplasmic surface of CydA. This C-terminal half of the Q-loop is essential for folding and stability of the CydA subunits of the L-subfamily bd oxidases 26 , 27 . Several homologs, including the one from M. tuberculosis , cannot be clearly assigned to either of these two subfamilies (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique structural framework and enables rational drug design to combat TB

Safarian

Opel-Reading

et al. 2021

Nat Commun

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New drugs are urgently needed to combat the global TB epidemic. Targeting simultaneously multiple respiratory enzyme complexes of Mycobacterium tuberculosis is regarded as one of the most effective treatment options to shorten drug administration regimes, and reduce the opportunity for the emergence of drug resistance. During infection and proliferation, the cytochrome bd oxidase plays a crucial role for mycobacterial pathophysiology by maintaining aerobic respiration at limited oxygen concentrations. Here, we present the cryo-EM structure of the cytochrome bd oxidase from M. tuberculosis at 2.5 Å. In conjunction with atomistic molecular dynamics (MD) simulation studies we discovered a previously unknown MK-9-binding site, as well as a unique disulfide bond within the Q-loop domain that defines an inactive conformation of the canonical quinol oxidation site in Actinobacteria. Our detailed insights into the long-sought atomic framework of the cytochrome bd oxidase from M. tuberculosis will form the basis for the design of highly specific drugs to act on this enzyme.

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Section: Resultsmentioning

confidence: 99%

The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique structural framework and enables rational drug design to combat TB

Safarian

Opel-Reading

et al. 2021

Nat Commun

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“…The family of bd oxidases is divided into L (long) and S (small)-subfamilies depending on the length of the periplasmic Q-loop 2 . Members of the L-subfamily harbor a C-terminal insertion in the Q-loop of about 60 residues that is essential for structural stability 32 , 33 . The N-terminal part of the Q-loop is involved in quinone binding 21 .…”

Section: Resultsmentioning

confidence: 99%

“…However, as shown here, this is not the case but it should be kept in mind that the incompletely resolved Q-loop belongs to a bd oxidase from the S-subfamily and shows in part a conformation different from that of other bd oxidases 43 . Due to its different length the Q-loop can be exchanged between E. coli bd -I and bd -II but not between E. coli bd -I and the G. thermodenitrificans enzyme 32 , 33 . The inhibitor aurachin is bound in a hydrophobic pocket provided by the Q-loop and TM helices 6 and 7 of AppC (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structure of Escherichia coli cytochrome bd-II type oxidase with bound aurachin D

et al. 2021

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Cytochrome bd quinol:O2 oxidoreductases are respiratory terminal oxidases so far only identified in prokaryotes, including several pathogenic bacteria. Escherichia coli contains two bd oxidases of which only the bd-I type is structurally characterized. Here, we report the structure of the Escherichia coli cytochrome bd-II type oxidase with the bound inhibitor aurachin D as obtained by electron cryo-microscopy at 3 Å resolution. The oxidase consists of subunits AppB, C and X that show an architecture similar to that of bd-I. The three heme cofactors are found in AppC, while AppB is stabilized by a structural ubiquinone-8 at the homologous positions. A fourth subunit present in bd-I is lacking in bd-II. Accordingly, heme b595 is exposed to the membrane but heme d embedded within the protein and showing an unexpectedly high redox potential is the catalytically active centre. The structure of the Q-loop is fully resolved, revealing the specific aurachin binding.

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“…It has two parts, one associated with the N-terminal domain (Q N ) and the other with the C-terminal domain (Q C ). The Q N -loop plays a functional role in the binding and oxidation of the quinol 27 , 28 and the Q C -loop is needed for the assembly/stability of the enzyme 22 , 23 , 25 .…”

Section: Resultsmentioning

confidence: 99%

Cryo-EM structure of mycobacterial cytochrome bd reveals two oxygen access channels

et al. 2021

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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.

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The long Q‐loop of Escherichia coli cytochrome bd oxidase is required for assembly and structural integrity

Cited by 19 publications

References 27 publications

The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique structural framework and enables rational drug design to combat TB

The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique structural framework and enables rational drug design to combat TB

Structure of Escherichia coli cytochrome bd-II type oxidase with bound aurachin D

Cryo-EM structure of mycobacterial cytochrome bd reveals two oxygen access channels

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