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Cited by 1Enzyme Structure and FunctionTuberculosis Research and EpidemiologyMetalloenzymes and iron-sulfur proteins

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Structural basis for EtfD-mediated coupling of β-oxidation and the respiratory chain in mycobacteria

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Courbon, Gautier M, Makarov, Vadim, Cole, Stewart T, Schnapinger, Dirk, Ehrt, Sabine, Rubinstein, John L·2026·The EMBO Journal
DOI 10.1038/s44318-026-00726-yPMC PMC12132442

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Abstract

Targeting β-oxidation has been proposed as a strategy for shortening tuberculosis (TB) treatment by killing non-replicating Mycobacterium tuberculosis within granulomas where the pathogen relies on host-derived lipids. The protein EtfD is thought to couple β-oxidation of fatty acids with the respiratory chain in mycobacteria. However, the structure of EtfD is not known and, as the presumed link between two complex processes, its activity has been difficult to measure, impeding its exploitation as a drug target. Here we show that Mycobacterium smegmatis , a fast growing and nonpathogenic model for M. tuberculosis , relies on EtfD for extracting energy from β-oxidation. The electron cryomicroscopy structure of M. smegma tis EtfD reveals an unusual linear [3Fe-4S] cluster that has not been seen in other protein structures, and suggests how EtfD transfers electrons from β-oxidation to the respiratory chain. We devised an assay that couples EtfD activity to a fluorescent readout of proton pumping by the respiratory chain, which can be used to identify compounds that block mycobacteria from using β-oxidation to power oxidative phosphorylation.

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Metadata

Authors
Courbon, G. M., Makarov, V., Cole, S. T., Schnapinger, D., Ehrt, S., & Rubinstein, J. L.
Affiliations
  • University of Toronto (CA)
  • Russian Academy of Sciences (RU)
  • University of Oxford (GB)
  • Weill Cornell Medicine (US)
Corresponding author
  • Courbon, Gautier M
  • Rubinstein, John L
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2026-03-17
Volume
45
Issue
8
Pages
2785-2807
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/s44318-026-00726-y
PMC
PMC12132442
OpenAlex
W7138343717
Cited by
1
References
3
Citations by year
2026: 1
FWCI
1.36
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • CIHR | CIHR Skin Research Training Centre (PJT191893)
  • HHS | National Institutes of Health (AI143575)
  • Bill and Melinda Gates Foundation (INV-055896, INV-055894)
  • Canada Research Chairs
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Metalloenzymes and iron-sulfur proteins
Keywords
Mycobacterium smegmatis, Mycobacterium tuberculosis, fatty acid beta-oxidation, electron transport chain, [3Fe-4S] cluster, electron transfer, oxidative phosphorylation, proton translocation, tuberculosis drug targets, non-replicating mycobacteria

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