Molecular dynamics simulations in: High-resolution structures with bound Mn2+ and Cd2+ map the metal import pathway in an Nramp transporter

Transporters of the Nramp (Natural resistance-associated macrophage
protein) family import divalent transition metal ions into cells of most
organisms. By supporting metal homeostasis, Nramps prevent disorders
related to metal insufficiency or overload. Previous studies revealed that
Nramps take on a LeuT fold and identified the metal-binding site. We
present high- resolution structures of Deinococcus
radiodurans Nramp in three stable conformations of the transport
cycle revealing that global conformational changes are supported by
distinct coordination geometries of its physiological substrate, Mn2+,
across conformations and conserved networks of polar residues lining the
inner and outer gates. A Cd2+-bound structure highlights differences in
coordination geometry for Mn2+ and Cd2+. Measurements of metal
binding using isothermal titration calorimetry indicate that the
thermodynamic landscape for binding and transporting physiological metals
like Mn2+ is different and more robust to perturbation than for
transporting the toxic Cd2+ metal.