Abstract
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.
Highlights
New drugs are urgently needed to combat the global TB epidemic
The cytochrome bd oxidase from M. tuberculosis was recombinantly produced in a Mycobacterium smegmatis mc[2 155] ΔcydAB strain harboring a markerless deletion of its chromosomal cytochrome bd oxidase (ΔcydAB)
The spectral properties of these hemes closely match those previously reported for the cytochrome bd oxidases of E. coli and Azotobacter vinelandii[20,21,22,23]
Summary
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. Targeting simultaneously multiple respiratory enzyme complexes in Mycobacterium tuberculosis is regarded as one of the most effective options to treat TB, shorten drug administration regimes, and reduce the opportunity for the emergence of drug resistance[5,6]. In this light, new lines of evidence point to a crucial role of the cytochrome bd oxidase for mycobacterial pathophysiology[7,8,9,10,11]. We present the cryo-EM structure of the bd oxidase from M. tuberculosis at 2.5 Å resolution which reveals a previously unknown MK-9 binding site at heme b595
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