{
  "abstract": "Active transporters move solutes uphill by harnessing the free energy stored in ATP or ion-motive gradients. A central tenet of molecular pharmacology is that orthosteric and allosteric inhibitors of active transporters act by slowing the transport cycle. We test this foundational premise, previously supported by ensemble-average data, at the single-molecule level. Using endogenous mammalian-brain V-ATPase, we show that bulk acidification can be abolished without any reduction in the single-molecule proton-transport rate. Instead, inhibitors predominantly promote reversible excursions outside the canonical transport cycle into ultralong-lived inactive modes. Overall, our findings establish the existence of two orthogonal axes of pharmacological control (on-cycle catalytic rates and off-cycle mode occupancy) that can be selectively or jointly actuated for precision drug design and likely generalize to other active transporters.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.",
    "Illum Biotech, Copenhagen, Denmark.",
    "Cancelight, Munich, Germany.",
    "Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.",
    "Department of Mathematics, University of Manchester, Manchester, United Kingdom.",
    "Department of Mathematics, University of Copenhagen, Copenhagen, Denmark.",
    "Laboratory of Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.",
    "Center of Membrane Biochemistry and Lipid Research, Dresden University of Technology, Dresden, Germany.",
    "Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.",
    "Collaborative Research Center 1690(CRC1690), University of Göttingen, Göttingen, Germany.",
    "Cluster of Excellence \"Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells\" (MBExC), Georg-August-University Göttingen, Göttingen, Germany.",
    "Department of Chemistry, University of Copenhagen, Copenhagen, Denmark. stamou@chem.ku.dk.",
    "Illum Biotech, Copenhagen, Denmark. stamou@chem.ku.dk."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Eleftherios Kosmidis",
      "orcid": "0000-0001-8204-3036"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Maria Fokaeos",
      "orcid": "0009-0004-4426-9981"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Christopher G Shuttle",
      "orcid": "0000-0002-5254-7759"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Michael Isselstein"
    },
    {
      "affs": [
        0
      ],
      "name": "Alessandra Narducci",
      "orcid": "0000-0003-0453-6681"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Aleksander Cvjetkovic",
      "orcid": "0000-0002-9131-9791"
    },
    {
      "affs": [
        4
      ],
      "name": "Peter J Johnson"
    },
    {
      "affs": [
        5
      ],
      "name": "Jesper L Pedersen",
      "orcid": "0000-0003-2308-5548"
    },
    {
      "affs": [
        6
      ],
      "name": "Reinhard Jahn",
      "orcid": "0000-0003-1542-3498"
    },
    {
      "affs": [
        7,
        8,
        9,
        10
      ],
      "name": "Julia Preobraschenski"
    },
    {
      "affs": [
        11,
        12
      ],
      "name": "Dimitrios Stamou",
      "orcid": "0000-0001-8456-8995"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/81d728hn3p8qs.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-78028-4",
  "fulltext_url": "https://europepmc.org/articles/PMC13728143",
  "id": "81d728hn3p8qs",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://europepmc.org/article/MED/42971968",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|ATP Synthase and ATPases Research"
    ]
  ],
  "openalex": "W7214628886",
  "pdf_url": "https://europepmc.org/articles/PMC13728143?pdf=render",
  "pmcid": "PMC13728143",
  "pmid": "42971968",
  "published": "2026-09-28",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/81d728hn3p8qs.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T15:20:44Z",
      "native_id": "MED:42971968",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42971968"
    },
    {
      "first_seen": "2026-11-06T12:23:53Z",
      "native_id": "PMC13728143",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41467-026-78028-4"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|ATP Synthase and ATPases Research",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Orthosteric and allosteric inhibition of the brain V-ATPase outside the alternating-access cycle.",
  "title_text": "Orthosteric and allosteric inhibition of the brain V-ATPase outside the alternating-access cycle.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:21:11Z",
  "url": "https://research.draconitic.com/paper/81d728hn3p8qs",
  "venue": "Nature communications",
  "versions": []
}