6TL2

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

6TL2 の概要

• エントリーDOI: 10.2210/pdb6tl2/pdb
• 分子名称: Divalent metal cation transporter MntH, [3-bromanyl-5-(carbamimidoylsulfanylmethyl)phenyl]methyl carbamimidothioate (2 entities in total)
• 機能のキーワード: inhibitor complex, transport protein
• 由来する生物種: Eremococcus coleocola ACS-139-V-Col8
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 54031.47

構造登録者

Manatschal, C.,Dutzler, R. (登録日: 2019-11-29, 公開日: 2019-12-18, 最終更新日: 2024-01-24)

主引用文献

Manatschal, C.,Pujol-Gimenez, J.,Poirier, M.,Reymond, J.L.,Hediger, M.A.,Dutzler, R.
Mechanistic basis of the inhibition of SLC11/NRAMP-mediated metal ion transport by bis-isothiourea substituted compounds.
Elife, 8:-, 2019

PubMed 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.

PubMed: 31804182
DOI: 10.7554/eLife.51913

実験手法

X-RAY DIFFRACTION (3.8 Å)