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

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-substitute...

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Autores principales: Manatschal, Cristina, Pujol-Giménez, Jonai, Poirier, Marion, Reymond, Jean-Louis, Hediger, Matthias A, Dutzler, Raimund
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917499/
https://www.ncbi.nlm.nih.gov/pubmed/31804182
http://dx.doi.org/10.7554/eLife.51913
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author Manatschal, Cristina
Pujol-Giménez, Jonai
Poirier, Marion
Reymond, Jean-Louis
Hediger, Matthias A
Dutzler, Raimund
author_facet Manatschal, Cristina
Pujol-Giménez, Jonai
Poirier, Marion
Reymond, Jean-Louis
Hediger, Matthias A
Dutzler, Raimund
author_sort Manatschal, Cristina
collection PubMed
description 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.
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spelling pubmed-69174992019-12-18 Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds Manatschal, Cristina Pujol-Giménez, Jonai Poirier, Marion Reymond, Jean-Louis Hediger, Matthias A Dutzler, Raimund eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2019-12-05 /pmc/articles/PMC6917499/ /pubmed/31804182 http://dx.doi.org/10.7554/eLife.51913 Text en © 2019, Manatschal et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Manatschal, Cristina
Pujol-Giménez, Jonai
Poirier, Marion
Reymond, Jean-Louis
Hediger, Matthias A
Dutzler, Raimund
Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds
title Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds
title_full Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds
title_fullStr Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds
title_full_unstemmed Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds
title_short Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds
title_sort mechanistic basis of the inhibition of slc11/nramp-mediated metal ion transport by bis-isothiourea substituted compounds
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917499/
https://www.ncbi.nlm.nih.gov/pubmed/31804182
http://dx.doi.org/10.7554/eLife.51913
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