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  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, S., Opel-Reading, H. K., Wu, D., Mehdipour, A. R., Hards, K., Harold, L. H., et al. (2021). The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique structural framework and enables rational drug design to combat TB. Nature Communications, 12(1): 5236. doi:10.1038/s41467-021-25537-z.

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 Creators:
Safarian, Schara1, Author           
Opel-Reading, Helen K.2, Author
Wu, Di1, Author           
Mehdipour, Ahmad Reza3, Author           
Hards, Kiel4, Author
Harold, Liam, H.4, Author
Radloff, Melanie1, Author           
Stewart, Ian5, Author
Welsch, Sonja6, Author           
Hummer, Gerhard3, 7, Author           
Cook, Gregory M.4, Author
Krause, Kurt L.2, Author
Michel, Hartmut1, Author           
Affiliations:
1Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society, ou_2068290              
2Department of Biochemistry, University of Otago, Dunedin, New Zealand, ou_persistent22              
3Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              
4Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand, ou_persistent22              
5Department of Chemistry, University of Otago, Dunedin, New Zealand, ou_persistent22              
6Central Electron Microscopy Facility, Max Planck Institute of Biophysics, Max Planck Society, ou_3249263              
7Institute of Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany, ou_persistent22              

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Free keywords: Bacterial structural biology; Bioenergetics; Cryoelectron microscopy; Structural biology
 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.

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Language(s): eng - English
 Dates: 2021-04-292021-08-172021-09-02
 Publication Status: Published online
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-021-25537-z
PMID: 34475399
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 12 (1) Sequence Number: 5236 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723