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

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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

(2019) Coordinates and structure factors
Protein Data Bank, 6TL2.

http://www.rcsb.org/structure/6TL2

Article and author information

Author details

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.
Jonai Pujol-Giménez

Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9951-1390
Marion Poirier

Department of Chemistry and Biochemisty, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Jean-Louis Reymond

Department of Chemistry and Biochemisty, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Matthias A Hediger

Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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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.