Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds
- University of Zürich, Switzerland
- 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
Article and author information
Author details
Jonai Pujol-Giménez
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.
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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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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