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The Mycobacterium smegmatis bd -II terminal oxidase employs a carboxylate shift mechanism
Open accessPreprint — published as 10.1073/pnas.2515348123 · Paper page
Abstract
Cytochrome bd is a terminal oxidase expressed under low oxygen conditions and central for the survival of many pathogens. Here we characterise the first qOR-2 type bd oxidase, the cyt bd -II from Mycobacterium smegmatis , by combining biochemical studies with cryo-electron microscopy (cryo-EM), and multiscale simulations. By over-expressing the appCB operon in its native host, we produce a highly active bd -II ( k cat =30 e - s -1 ) that together with a high-resolution (2.8 Å) cryo-EM structure and multiscale simulations reveal unique proton pathways and oxygen channels responsible for its function. We propose that O 2 -scavenging activates a pH-dependent molecular switch, involving coordination changes of heme d and surrounding bulky residues that regulate substrate access into the active site. Taken together, our findings provide detailed mechanistic insight of qOR-2 type bd oxidases, and a basis for understanding the evolution of the superfamily.
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Metadata
- Authors
- Kovalova, T., Janczak, M., Gamiz-Hernandez, A. P., Lundin, D., Sharma, S., Vilhjálmsdóttir, J., Sjöstrand, D., Kaila, V. R. I., Högbom, M., & Ädelroth, P.
- Affiliations
- Department of Biochemistry and Biophysics, Stockholm University, 116 91 Stockholm, Sweden
- Stockholm University (SE)
- Corresponding author
- Janczak, Mateusz
- Kaila, Ville R. I.
- Högbom, Martin
- Ädelroth, Pia
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- openRxiv
- Published
- 2025-06-23
- Volume
- 123
- Issue
- 11
- Pages
- e2515348123-e2515348123
- ISSN
- 0027-8424 (ISSN-L)
- PMC
- PMC12994193
- OpenAlex
- W7134903783
- Cited by
- 1
- References
- 1
- Citations by year
- 2026: 1
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Funders
- Knut and Alice Wallenberg Foundation (2019.0043, 2023.0201, 2024.0220)
- Topics
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Metalloenzymes and iron-sulfur proteins
- Keywords
- terminal oxidase, Mycobacterium smegmatis, proton pathway, enzyme mechanism
- MeSH terms
- Bacterial Proteins, Cytochrome b Group, Heme, Hydrogen-Ion Concentration, Models, Molecular, Oxidoreductases, Oxygen, Mycobacterium smegmatis, Catalytic Domain, Cryoelectron Microscopy
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