6tl2

Crystal structure of Eremococcus coleocola manganese transporter in complex with an aromatic bis-isothiourea substituted compound

spinqualitylabelsall models 6tl2, resolution 3.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tl2 is a 1 chain structure with sequence from Eremococcus coleocola ACS-139-V-Col8. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.8Å Ligands: NJZ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function E4KPW4_9LACT H(+)-stimulated, divalent metal cation uptake system.[HAMAP-Rule:MF_00221] Publication Abstract from PubMed 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. Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds.,Manatschal C, Pujol-Gimenez J, Poirier M, Reymond JL, Hediger MA, Dutzler R Elife. 2019 Dec 5;8. pii: 51913. doi: 10.7554/eLife.51913. PMID:31804182 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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