Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds

  1. Cristina Manatschal  Is a corresponding author
  2. Jonai Pujol-Giménez
  3. Marion Poirier
  4. Jean-Louis Reymond
  5. Matthias A Hediger
  6. Raimund Dutzler  Is a corresponding author
  1. University of Zürich, Switzerland
  2. University of Bern, Switzerland

Abstract

In humans, the divalent metal-ion transporter-1 (DMT1) mediates the transport of ferrous iron across the apical membrane of enterocytes. Hence, its inhibition could be beneficial for the treatment of iron overload disorders. Here we characterize the interaction of aromatic bis-isothiourea-substituted compounds with human DMT1 and its prokaryotic homologue EcoDMT. Both transporters are inhibited by a common competitive mechanism with potencies in the low micromolar range. The crystal structure of EcoDMT in complex with a brominated derivative defines the binding of the inhibitor to an extracellular pocket of the transporter in direct contact with residues of the metal ion coordination site, thereby interfering with substrate loading and locking the transporter in its outward-facing state. Mutagenesis and structure-activity relationships further support the observed interaction mode and reveal species-dependent differences between pro- and eukaryotic transporters. Together, our data provide the first detailed mechanistic insight into the pharmacology of SLC11/NRAMP transporters.

Data availability

Coordinates and structure factors have been deposited with the PDB under Accession Code 6TL2

The following data sets were generated

Article and author information

Author details

  1. Cristina Manatschal

    Department of Biochemistry, University of Zürich, Zürich, Switzerland
    For correspondence
    c.manatschal@bioc.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
  2. Jonai Pujol-Giménez

    Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9951-1390
  3. Marion Poirier

    Department of Chemistry and Biochemisty, University of Bern, Bern, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Jean-Louis Reymond

    Department of Chemistry and Biochemisty, University of Bern, Bern, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Matthias A Hediger

    Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Raimund Dutzler

    Department of Biochemistry, University of Zürich, Zürich, Switzerland
    For correspondence
    dutzler@bioc.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2193-6129

Funding

Swiss National Science Foundation (NCCR TransCure)

  • Jean-Louis Reymond
  • Matthias A Hediger
  • Raimund Dutzler

Swiss National Science Foundation (SNF grant 310030_182272)

  • Matthias A Hediger

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. László Csanády, Semmelweis University, Hungary

Publication history

  1. Received: September 16, 2019
  2. Accepted: November 22, 2019
  3. Accepted Manuscript published: December 5, 2019 (version 1)
  4. Version of Record published: December 17, 2019 (version 2)

Copyright

© 2019, Manatschal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Cristina Manatschal
  2. Jonai Pujol-Giménez
  3. Marion Poirier
  4. Jean-Louis Reymond
  5. Matthias A Hediger
  6. Raimund Dutzler
(2019)
Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds
eLife 8:e51913.
https://doi.org/10.7554/eLife.51913
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