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Cited by 1Ion Transport and Channel RegulationIon channel regulation and functionProtein Structure and Dynamics

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Molecular simulations meet personalized medicine: The mechanism of action of CLC-5 antiporter and the origin of Dent's disease

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Macaluso, Veronica, Pérez, Carles, Soliva, Robert, Westermaier, Yvonne, Díaz, Lucía, Wieczór, Miłosz, Orozco, Modesto·2025·PNAS Nexus
DOI 10.1093/pnasnexus/pgaf353PMC PMC12624513

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Abstract

ClC-5 is a Cl−/H+ antiporter crucial for the homeostasis of the entire organism, and whose functional deficiencies cause pathologies such as Dent's disease, a rare genetic disorder that can have lethal consequences. While the clinical aspects of the pathology are known, its molecular basis is elusive, which hampers the development of potential therapies. We present here a systematic study, where we explore the mechanism of transport of ClC-5, deciphering the choreography of structural changes required for the transport of chloride ions and protons in opposing directions. Once the mechanism is determined, we explore how the 523ΔVal deletion linked to Dent's disease hampers the correct functioning of the transporter, despite having a very minor structural impact. Our study highlights how state-of-the-art simulation methods can shed light on the origin of rare diseases and explore targets for personalized medicine.

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Metadata

Authors
Macaluso, V., Pérez, C., Soliva, R., Westermaier, Y., Díaz, L., Wieczór, M., & Orozco, M.
Affiliations
  • Institute for Research in Biomedicine (ES)
  • Nostrum Biodiscovery , Av. de Josep Tarradellas 8-10, 08029 Barcelona ,
  • Gdańsk University of Technology (PL)
Corresponding author
Orozco, Modesto
ORCID
Venue
PNAS Nexus
Publisher
Oxford University Press (OUP)
Published
2025-10-31
Volume
4
Issue
11
Pages
pgaf353-pgaf353
ISSN
2752-6542 (ISSN-L)
DOI
10.1093/pnasnexus/pgaf353
PMC
PMC12624513
OpenAlex
W4415862285
Cited by
1
References
1
Citations by year
2026: 1
FWCI
0.30
Type
journal article
Language
en
Open access
Licence
Locations
  • PNAS Nexus (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
Funders
  • ASDENT Foundation
  • Spanish Ministry of Science, Innovation and Universities (PID2021-122478NB-I00, PCI2022-134976-2)
  • Torres Quevedo Program (PTQ2018-009992, PTQ2018-009991)
  • H2020 European Commission's Center of Excellence for HPC “BioExcel-2
  • Centre of Excellence for Computational Biomolecular Research (823830)
  • European Regional Development Fund
  • ERFD Operative Programme for Catalonia
  • Catalan Government AGAUR (SGR2017-134)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
ClC-5, Dent's disease, ion transport mechanism, rare genetic disorders, personalized medicine, molecular simulation, chloride homeostasis

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