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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eLife Sciences Publications Ltd
2019-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/51913 |
| _version_ | 1818026877430792192 |
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| author | Cristina Manatschal Jonai Pujol-Giménez Marion Poirier Jean-Louis Reymond Matthias A Hediger Raimund Dutzler |
| author_facet | Cristina Manatschal Jonai Pujol-Giménez Marion Poirier Jean-Louis Reymond Matthias A Hediger Raimund Dutzler |
| author_sort | Cristina Manatschal |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-10T04:38:59Z |
| format | Article |
| id | doaj.art-a99a0f3c47824ac1a024d928680243e4 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:38:59Z |
| publishDate | 2019-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj.art-a99a0f3c47824ac1a024d928680243e42022-12-22T02:01:56ZengeLife Sciences Publications LtdeLife2050-084X2019-12-01810.7554/eLife.51913Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compoundsCristina Manatschal0https://orcid.org/0000-0002-4907-7303Jonai Pujol-Giménez1https://orcid.org/0000-0002-9951-1390Marion Poirier2Jean-Louis Reymond3https://orcid.org/0000-0003-2724-2942Matthias A Hediger4Raimund Dutzler5https://orcid.org/0000-0002-2193-6129Department of Biochemistry, University of Zurich, Zurich, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; Membrane Transport Discovery Lab, Department of Nephrology and Hypertension, Inselspital, University of Bern, Bern, Switzerland; Department of Biomedical Research, University of Bern, Bern, SwitzerlandDepartment of Chemistry and Biochemistry, University of Bern, Bern, SwitzerlandDepartment of Chemistry and Biochemistry, University of Bern, Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; Membrane Transport Discovery Lab, Department of Nephrology and Hypertension, Inselspital, University of Bern, Bern, Switzerland; Department of Biomedical Research, University of Bern, Bern, SwitzerlandDepartment of Biochemistry, University of Zurich, Zurich, SwitzerlandIn 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.https://elifesciences.org/articles/51913transition metal ion transporthemochromatosiscompetittive inhibitionX-ray crystallographyreconstitution |
| spellingShingle | Cristina Manatschal Jonai Pujol-Giménez Marion Poirier Jean-Louis Reymond Matthias A Hediger Raimund Dutzler Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds eLife transition metal ion transport hemochromatosis competittive inhibition X-ray crystallography reconstitution |
| 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 | transition metal ion transport hemochromatosis competittive inhibition X-ray crystallography reconstitution |
| url | https://elifesciences.org/articles/51913 |
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