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 (2019). Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds. eLife, 8 eLife Sciences Publications 10.7554/eLife.51913

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Pujol Gimenez, Jonai; Poirier, Marion; Reymond, Jean-Louis and Hediger, Matthias

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

ISSN:

2050-084X

Publisher:

eLife Sciences Publications

Language:

English

Submitter:

Verena de Serra Frazao-Bill

Date Deposited:

23 Dec 2019 14:01

Last Modified:

23 Dec 2019 14:17

Publisher DOI:

10.7554/eLife.51913

PubMed ID:

31804182

Additional Information:

Cristina Manatschal, Jonai Pujol-Giménez, Marion Poirier: these authors contributed equally to this work.

Uncontrolled Keywords:

E. coli X-ray crystallography biochemistry chemical biology competittive inhibition hemochromatosis molecular biophysics reconstitution structural biology transition metal ion transport

BORIS DOI:

10.7892/boris.137207

URI:

https://boris.unibe.ch/id/eprint/137207

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