{"entity": "researcher", "timestamp": "2026-06-07T08:02:11.637Z", "family": "Brzezinski", "given": "Peter", "initials": "P", "orcid": "0000-0003-3860-4988", "affiliations": ["Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20"}}, "publications": [{"entity": "publication", "iuid": "87ba0d1a6c6c409db86213933d82eaeb", "links": {"self": {"href": "https://publications.scilifelab.se/publication/87ba0d1a6c6c409db86213933d82eaeb.json"}, "display": {"href": "https://publications.scilifelab.se/publication/87ba0d1a6c6c409db86213933d82eaeb"}}, "title": "Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide.", "authors": [{"family": "Kovalova", "given": "Terezia", "initials": "T", "orcid": "0000-0002-0144-2463", "researcher": {"href": "https://publications.scilifelab.se/researcher/28a04987c43944d788c125a1dfd15828.json"}}, {"family": "Kr\u00f3l", "given": "Sylwia", "initials": "S"}, {"family": "Gamiz-Hernandez", "given": "Ana P", "initials": "AP", "orcid": "0000-0002-0961-328X", "researcher": {"href": "https://publications.scilifelab.se/researcher/8021ee901c9442e792bba76d38984d4a.json"}}, {"family": "Sj\u00f6strand", "given": "Dan", "initials": "D"}, {"family": "Kaila", "given": "Ville R I", "initials": "VRI", "orcid": "0000-0003-4464-6324", "researcher": {"href": "https://publications.scilifelab.se/researcher/cdcc63256cea406c9cb9cdaecc9cbcbe.json"}}, {"family": "Brzezinski", "given": "Peter", "initials": "P", "orcid": "0000-0003-3860-4988", "researcher": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20.json"}}, {"family": "H\u00f6gbom", "given": "Martin", "initials": "M", "orcid": "0000-0001-5574-9383", "researcher": {"href": "https://publications.scilifelab.se/researcher/d968fcccace74b689185bb9fa2d33bf8.json"}}], "type": "journal article", "published": "2024-11-19", "journal": {"title": "Proc. Natl. Acad. Sci. U.S.A.", "issn": "1091-6490", "volume": "121", "issue": "47", "pages": "e2412780121", "issn-l": "0027-8424"}, "abstract": "Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate that lansoprazole-a known gastric proton pump inhibitor and its intracellular metabolite, lansoprazole sulfide (LPZS)-are potential antituberculosis compounds. Yet, their inhibitory mechanism and site of action still remain unknown. Here, we combine biochemical, computational, and structural approaches to probe the interaction of LPZS with the respiratory chain supercomplex III2IV2 of Mycobacterium smegmatis, a close homolog of Mycobacterium tuberculosis supercomplex. We show that LPZS binds to the Qo cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We solve high-resolution (2.6 \u00c5) cryo-electron microscopy (cryo-EM) structures of the supercomplex with bound LPZS that together with microsecond molecular dynamics simulations, directed mutagenesis, and functional assays reveal key interactions that stabilize the inhibitor, but also how mutations can lead to the emergence of drug resistance. Our combined findings reveal an inhibitory mechanism of LPZS and provide a structural basis for drug development against tuberculosis.", "doi": "10.1073/pnas.2412780121", "pmid": "39531492", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11588064"}], "notes": [], "created": "2024-11-15T08:52:59.415Z", "modified": "2025-11-25T15:59:03.981Z"}, {"entity": "publication", "iuid": "88d3b144a82242fe917650dbb2327d3d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/88d3b144a82242fe917650dbb2327d3d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/88d3b144a82242fe917650dbb2327d3d"}}, "title": "Long-range charge transfer mechanism of the III2IV2 mycobacterial supercomplex.", "authors": [{"family": "Riepl", "given": "Daniel", "initials": "D", "orcid": "0000-0002-5641-3037", "researcher": {"href": "https://publications.scilifelab.se/researcher/9d319a620085414b92d1b92fb640ec72.json"}}, {"family": "Gamiz-Hernandez", "given": "Ana P", "initials": "AP", "orcid": "0000-0002-0961-328X", "researcher": {"href": "https://publications.scilifelab.se/researcher/8021ee901c9442e792bba76d38984d4a.json"}}, {"family": "Kovalova", "given": "Terezia", "initials": "T", "orcid": "0000-0002-0144-2463", "researcher": {"href": "https://publications.scilifelab.se/researcher/28a04987c43944d788c125a1dfd15828.json"}}, {"family": "Kr\u00f3l", "given": "Sylwia M", "initials": "SM"}, {"family": "Mader", "given": "Sophie L", "initials": "SL", "orcid": "0000-0002-3011-3319", "researcher": {"href": "https://publications.scilifelab.se/researcher/23c686122cd34cfe9a4ab53c925c246d.json"}}, {"family": "Sj\u00f6strand", "given": "Dan", "initials": "D"}, {"family": "H\u00f6gbom", "given": "Martin", "initials": "M", "orcid": "0000-0001-5574-9383", "researcher": {"href": "https://publications.scilifelab.se/researcher/d968fcccace74b689185bb9fa2d33bf8.json"}}, {"family": "Brzezinski", "given": "Peter", "initials": "P", "orcid": "0000-0003-3860-4988", "researcher": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20.json"}}, {"family": "Kaila", "given": "Ville R I", "initials": "VRI", "orcid": "0000-0003-4464-6324", "researcher": {"href": "https://publications.scilifelab.se/researcher/cdcc63256cea406c9cb9cdaecc9cbcbe.json"}}], "type": "journal article", "published": "2024-06-20", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "15", "issue": "1", "pages": "5276", "issn-l": "2041-1723"}, "abstract": "Aerobic life is powered by membrane-bound redox enzymes that shuttle electrons to oxygen and transfer protons across a biological membrane. Structural studies suggest that these energy-transducing enzymes operate as higher-order supercomplexes, but their functional role remains poorly understood and highly debated. Here we resolve the functional dynamics of the 0.7 MDa III2IV2 obligate supercomplex from Mycobacterium smegmatis, a close relative of M. tuberculosis, the causative agent of tuberculosis. By combining computational, biochemical, and high-resolution (2.3 \u00c5) cryo-electron microscopy experiments, we show how the mycobacterial supercomplex catalyses long-range charge transport from its menaquinol oxidation site to the binuclear active site for oxygen reduction. Our data reveal proton and electron pathways responsible for the charge transfer reactions, mechanistic principles of the quinone catalysis, and how unique molecular adaptations, water molecules, and lipid interactions enable the proton-coupled electron transfer (PCET) reactions. Our combined findings provide a mechanistic blueprint of mycobacterial supercomplexes and a basis for developing drugs against pathogenic bacteria.", "doi": "10.1038/s41467-024-49628-9", "pmid": "38902248", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11189923"}, {"db": "pii", "key": "10.1038/s41467-024-49628-9"}], "notes": [], "created": "2024-11-15T08:56:46.121Z", "modified": "2024-11-15T10:41:20.395Z"}, {"entity": "publication", "iuid": "b8cb11c9ab724b39ae85f957138ab6ad", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b8cb11c9ab724b39ae85f957138ab6ad.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b8cb11c9ab724b39ae85f957138ab6ad"}}, "title": "Structure and function of the S. pombe III-IV-cyt c supercomplex.", "authors": [{"family": "Moe", "given": "Agnes", "initials": "A", "orcid": "0000-0002-3328-763X", "researcher": {"href": "https://publications.scilifelab.se/researcher/1cf8d942c69c45c9b72872f0803d0c78.json"}}, {"family": "Dimogkioka", "given": "Anna-Roza", "initials": "AR"}, {"family": "Rapaport", "given": "Doron", "initials": "D"}, {"family": "\u00d6jemyr", "given": "Linda N\u00e4svik", "initials": "LN"}, {"family": "Brzezinski", "given": "Peter", "initials": "P", "orcid": "0000-0003-3860-4988", "researcher": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20.json"}}], "type": "journal article", "published": "2023-11-14", "journal": {"title": "Proc. Natl. Acad. Sci. U.S.A.", "issn": "1091-6490", "volume": "120", "issue": "46", "pages": "e2307697120", "issn-l": "0027-8424"}, "abstract": "The respiratory chain in aerobic organisms is composed of a number of membrane-bound protein complexes that link electron transfer to proton translocation across the membrane. In mitochondria, the final electron acceptor, complex IV (CIV), receives electrons from dimeric complex III (CIII2), via a mobile electron carrier, cytochrome c. In the present study, we isolated the CIII2CIV supercomplex from the fission yeast Schizosaccharomyces pombe and determined its structure with bound cyt. c using single-particle electron cryomicroscopy. A respiratory supercomplex factor 2 was found to be bound at CIV distally positioned in the supercomplex. In addition to the redox-active metal sites, we found a metal ion, presumably Zn2+, coordinated in the CIII subunit Cor1, which is encoded by the same gene (qcr1) as the mitochondrial-processing peptidase subunit \u03b2. Our data show that the isolated CIII2CIV supercomplex displays proteolytic activity suggesting a dual role of CIII2 in S. pombe. As in the supercomplex from S. cerevisiae, subunit Cox5 of CIV faces towards one CIII monomer, but in S. pombe, the two complexes are rotated relative to each other by ~45\u00b0. This orientation yields equal distances between the cyt. c binding sites at CIV and at each of the two CIII monomers. The structure shows cyt. c bound at four positions, but only along one of the two symmetrical branches. Overall, this combined structural and functional study reveals the integration of peptidase activity with the CIII2 respiratory system and indicates a two-dimensional cyt. c diffusion mechanism within the CIII2-CIV supercomplex.", "doi": "10.1073/pnas.2307697120", "pmid": "37939086", "labels": {"Cryo-EM": "Service"}, "xrefs": [], "notes": [], "created": "2023-11-16T12:00:11.293Z", "modified": "2023-11-16T12:00:11.586Z"}, {"entity": "publication", "iuid": "30ab3fb1ab844479954aed6baf02f080", "links": {"self": {"href": "https://publications.scilifelab.se/publication/30ab3fb1ab844479954aed6baf02f080.json"}, "display": {"href": "https://publications.scilifelab.se/publication/30ab3fb1ab844479954aed6baf02f080"}}, "title": "Cryo-EM structure and function of S. pombe complex IV with bound respiratory supercomplex factor.", "authors": [{"family": "Moe", "given": "Agnes", "initials": "A", "orcid": "0000-0002-3328-763X", "researcher": {"href": "https://publications.scilifelab.se/researcher/1cf8d942c69c45c9b72872f0803d0c78.json"}}, {"family": "\u00c4delroth", "given": "Pia", "initials": "P", "orcid": "0000-0003-0853-6785", "researcher": {"href": "https://publications.scilifelab.se/researcher/b798b3a524114a62b4132d17cb34f8ea.json"}}, {"family": "Brzezinski", "given": "Peter", "initials": "P", "orcid": "0000-0003-3860-4988", "researcher": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20.json"}}, {"family": "N\u00e4svik \u00d6jemyr", "given": "Linda", "initials": "L", "orcid": "0000-0001-9311-491X", "researcher": {"href": "https://publications.scilifelab.se/researcher/cc6373814a7f4f1a85b8724ba3c65043.json"}}], "type": "journal article", "published": "2023-02-16", "journal": {"title": "Commun Chem", "issn": "2399-3669", "volume": "6", "issue": "1", "pages": "32", "issn-l": null}, "abstract": "Fission yeast Schizosaccharomyces pombe serves as model organism for studying higher eukaryotes. We combined the use of cryo-EM and spectroscopy to investigate the structure and function of affinity purified respiratory complex IV (CIV) from S. pombe. The reaction sequence of the reduced enzyme with O2 proceeds over a time scale of \u00b5s-ms, similar to that of the mammalian CIV. The cryo-EM structure of CIV revealed eleven subunits as well as a bound hypoxia-induced gene 1 (Hig1) domain of respiratory supercomplex factor 2 (Rcf2). These results suggest that binding of Rcf2 does not require the presence of a CIII-CIV supercomplex, i.e. Rcf2 is a component of CIV. An AlphaFold-Multimer model suggests that the Hig1 domains of both Rcf1 and Rcf2 bind at the same site of CIV suggesting that their binding is mutually exclusive. Furthermore, the differential functional effect of Rcf1 or Rcf2 is presumably caused by interactions of CIV with their different non-Hig1 domain parts.", "doi": "10.1038/s42004-023-00827-3", "pmid": "36797353", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9935853"}, {"db": "pii", "key": "10.1038/s42004-023-00827-3"}], "notes": [], "created": "2023-03-07T18:51:19.194Z", "modified": "2023-03-07T18:51:19.320Z"}, {"entity": "publication", "iuid": "84dc535b12fa4c0198fd8f04cf4b2644", "links": {"self": {"href": "https://publications.scilifelab.se/publication/84dc535b12fa4c0198fd8f04cf4b2644.json"}, "display": {"href": "https://publications.scilifelab.se/publication/84dc535b12fa4c0198fd8f04cf4b2644"}}, "title": "The respiratory supercomplex from C. glutamicum.", "authors": [{"family": "Moe", "given": "Agnes", "initials": "A", "orcid": "0000-0002-3328-763X", "researcher": {"href": "https://publications.scilifelab.se/researcher/1cf8d942c69c45c9b72872f0803d0c78.json"}}, {"family": "Kovalova", "given": "Terezia", "initials": "T", "orcid": "0000-0002-0144-2463", "researcher": {"href": "https://publications.scilifelab.se/researcher/28a04987c43944d788c125a1dfd15828.json"}}, {"family": "Kr\u00f3l", "given": "Sylwia", "initials": "S"}, {"family": "Yanofsky", "given": "David J", "initials": "DJ"}, {"family": "Bott", "given": "Michael", "initials": "M"}, {"family": "Sj\u00f6strand", "given": "Dan", "initials": "D"}, {"family": "Rubinstein", "given": "John L", "initials": "JL", "orcid": "0000-0003-0566-2209", "researcher": {"href": "https://publications.scilifelab.se/researcher/771d163fc4b543669ee8fd1148bfe24d.json"}}, {"family": "H\u00f6gbom", "given": "Martin", "initials": "M", "orcid": "0000-0001-5574-9383", "researcher": {"href": "https://publications.scilifelab.se/researcher/d968fcccace74b689185bb9fa2d33bf8.json"}}, {"family": "Brzezinski", "given": "Peter", "initials": "P", "orcid": "0000-0003-3860-4988", "researcher": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20.json"}}], "type": "journal article", "published": "2022-03-03", "journal": {"title": "Structure", "issn": "1878-4186", "volume": "30", "issue": "3", "pages": "338-349.e3", "issn-l": "0969-2126"}, "abstract": "Corynebacterium glutamicum is a preferentially aerobic gram-positive bacterium belonging to the phylum Actinobacteria, which also includes the pathogen Mycobacterium tuberculosis. In these bacteria, respiratory complexes III and IV form a CIII2CIV2 supercomplex that catalyzes oxidation of menaquinol and reduction of dioxygen to water. We isolated the C. glutamicum supercomplex and used cryo-EM to determine its structure at 2.9 \u00c5 resolution. The structure shows a central CIII2 dimer flanked by a CIV on two sides. A menaquinone is bound in each of the QN and QP sites in each CIII and an additional menaquinone is positioned \u223c14 \u00c5 from heme bL. A di-heme cyt. cc subunit electronically connects each CIII with an adjacent CIV, with the Rieske iron-sulfur protein positioned with the iron near heme bL. Multiple subunits interact to form a convoluted sub-structure at the cytoplasmic side of the supercomplex, which defines a path for proton transfer into CIV.", "doi": "10.1016/j.str.2021.11.008", "pmid": "34910901", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pii", "key": "S0969-2126(21)00420-2"}], "notes": [], "created": "2022-03-22T10:03:37.876Z", "modified": "2024-11-15T08:54:18.217Z"}, {"entity": "publication", "iuid": "92dba4d4ec6f45f9ad59022513e674eb", "links": {"self": {"href": "https://publications.scilifelab.se/publication/92dba4d4ec6f45f9ad59022513e674eb.json"}, "display": {"href": "https://publications.scilifelab.se/publication/92dba4d4ec6f45f9ad59022513e674eb"}}, "title": "Cryo-EM structure of the yeast respiratory supercomplex.", "authors": [{"family": "Rathore", "given": "Sorbhi", "initials": "S", "orcid": "0000-0001-9178-1006", "researcher": {"href": "https://publications.scilifelab.se/researcher/5c2293f9f60f44cfa47f1e3691c1309d.json"}}, {"family": "Berndtsson", "given": "Jens", "initials": "J", "orcid": "0000-0001-6627-8134", "researcher": {"href": "https://publications.scilifelab.se/researcher/7620a5c7c0f245a28771d57d7179abbd.json"}}, {"family": "Marin-Buera", "given": "Lorena", "initials": "L"}, {"family": "Conrad", "given": "Julian", "initials": "J"}, {"family": "Carroni", "given": "Marta", "initials": "M", "orcid": "0000-0002-7697-6427", "researcher": {"href": "https://publications.scilifelab.se/researcher/e7f1bc1767024368abcb11a83184994a.json"}}, {"family": "Brzezinski", "given": "Peter", "initials": "P", "orcid": "0000-0003-3860-4988", "researcher": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20.json"}}, {"family": "Ott", "given": "Martin", "initials": "M", "orcid": "0000-0001-6367-3091", "researcher": {"href": "https://publications.scilifelab.se/researcher/b27b582dbd2a47bcbb0fb3194277902a.json"}}], "type": "journal article", "published": "2019-01-00", "journal": {"title": "Nat. Struct. Mol. Biol.", "issn": "1545-9985", "volume": "26", "issue": "1", "pages": "50-57", "issn-l": "1545-9985"}, "abstract": "Respiratory chain complexes execute energy conversion by connecting electron transport with proton translocation over the inner mitochondrial membrane to fuel ATP synthesis. Notably, these complexes form multi-enzyme assemblies known as respiratory supercomplexes. Here we used single-particle cryo-EM to determine the structures of the yeast mitochondrial respiratory supercomplexes III 2IV and III2IV2, at 3.2-\u00c5 and 3.5-\u00c5 resolutions, respectively. We revealed the overall architecture of the supercomplex, which deviates from the previously determined assemblies in mammals; obtained a near-atomic structure of the yeast complex IV; and identified the protein-protein and protein-lipid interactions implicated in supercomplex formation. Take together, our results demonstrate convergent evolution of supercomplexes in mitochondria that, while building similar assemblies, results in substantially different arrangements and structural solutions to support energy conversion.", "doi": "10.1038/s41594-018-0169-7", "pmid": "30598556", "labels": {"Cryo-EM": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41594-018-0169-7"}], "notes": [], "created": "2019-01-03T16:38:40.124Z", "modified": "2021-06-21T13:49:53.118Z"}, {"entity": "publication", "iuid": "c43fdddf24ee4d548364cd7bb3c5885d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c43fdddf24ee4d548364cd7bb3c5885d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c43fdddf24ee4d548364cd7bb3c5885d"}}, "title": "Structure of a functional obligate complex III 2IV2 respiratory supercomplex from Mycobacterium smegmatis.", "authors": [{"family": "Wiseman", "given": "Benjamin", "initials": "B", "orcid": "0000-0002-2994-5839", "researcher": {"href": "https://publications.scilifelab.se/researcher/2098646fa9de4dbc8f7cca8aeabad319.json"}}, {"family": "Nitharwal", "given": "Ram Gopal", "initials": "RG"}, {"family": "Fedotovskaya", "given": "Olga", "initials": "O"}, {"family": "Sch\u00e4fer", "given": "Jacob", "initials": "J"}, {"family": "Guo", "given": "Hui", "initials": "H", "orcid": "0000-0001-7007-2876", "researcher": {"href": "https://publications.scilifelab.se/researcher/f6a0383b19ff4fe78c32a07079f90a51.json"}}, {"family": "Kuang", "given": "Qie", "initials": "Q"}, {"family": "Benlekbir", "given": "Samir", "initials": "S"}, {"family": "Sj\u00f6strand", "given": "Dan", "initials": "D"}, {"family": "\u00c4delroth", "given": "Pia", "initials": "P"}, {"family": "Rubinstein", "given": "John L", "initials": "JL", "orcid": "0000-0003-0566-2209", "researcher": {"href": "https://publications.scilifelab.se/researcher/771d163fc4b543669ee8fd1148bfe24d.json"}}, {"family": "Brzezinski", "given": "Peter", "initials": "P", "orcid": "0000-0003-3860-4988", "researcher": {"href": "https://publications.scilifelab.se/researcher/e3314030ecf94791a713a068d4926c20.json"}}, {"family": "H\u00f6gbom", "given": "Martin", "initials": "M", "orcid": "0000-0001-5574-9383", "researcher": {"href": "https://publications.scilifelab.se/researcher/d968fcccace74b689185bb9fa2d33bf8.json"}}], "type": "journal article", "published": "2018-12-00", "journal": {"title": "Nat. Struct. Mol. Biol.", "issn": "1545-9985", "volume": "25", "issue": "12", "pages": "1128-1136", "issn-l": "1545-9985"}, "abstract": "In the mycobacterial electron-transport chain, respiratory complex III passes electrons from menaquinol to complex IV, which in turn reduces oxygen, the terminal acceptor. Electron transfer is coupled to transmembrane proton translocation, thus establishing the electrochemical proton gradient that drives ATP synthesis. We isolated, biochemically characterized, and determined the structure of the obligate III 2IV2 supercomplex from Mycobacterium smegmatis, a model for Mycobacterium tuberculosis. The supercomplex has quinol:O2 oxidoreductase activity without exogenous cytochrome c and includes a superoxide dismutase subunit that may detoxify reactive oxygen species produced during respiration. We found menaquinone bound in both the Qo and Qi sites of complex III. The complex III-intrinsic diheme cytochrome cc subunit, which functionally replaces both cytochrome c1 and soluble cytochrome c in canonical electron-transport chains, displays two conformations: one in which it provides a direct electronic link to complex IV and another in which it serves as an electrical switch interrupting the connection.", "doi": "10.1038/s41594-018-0160-3", "pmid": "30518849", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pii", "key": "10.1038/s41594-018-0160-3"}], "notes": [], "created": "2019-08-01T08:29:50.182Z", "modified": "2021-06-21T13:56:08.387Z"}]}