(A) Model of conformational change: The metal ion reaches the outward-open binding site via the vestibule between TMs 1b, 6a, 10, 3, and 8. TM6a and 10 bend inward to close the vestibule in the inward-occluded conformation. TM6a’s inward bend pulls on TM5 via extracellular loop 5–6 to initiate opening of the inner gate. Finally, TM1a swings away from TM6b to open the intracellular vestibule into which the metal diffuses. (B) Superposition of outward- (gold) and inward-open (teal) conformations illustrate key movements by TMs 1, 5, 6, and 10. (C) Overall DraNramp transport model under prevailing physiological conditions (negative inside membrane potential, acidic-outside pH gradient): While metal transport requires complete conformational cycling, proton uniport occurs through the outward-open state. Metal-stimulated proton transport may follow the same pathway as proton uniport. (D) Proton transport model: A proton transits the external vestibule to reach the binding site near the membrane center and initially binds to D56. Metal enters through the same passageway, ejecting the proton, which then passes to D131, with H232 and E134 facilitating the transfer. The proton ultimately reaches the cytoplasm through the polar network between TMs 3, 4, 8, and 9, while the metal must await a bulk conformational change that opens a separate pathway between TMs 1a, 2, 5, 6b, 7, and 8. Proton uniport follows the same route, with the D56-D131 transfer occurring at a slower rate without metal substrate. (E) Model for metal coordination during the transport process: the metal initially binds in the outward-open state to D56, N59, M230 sidechains and the A53 carbonyl, shedding all but two water ligands. As the outward metal-permeation pathway closes, Q378 and the A227 carbonyl displace the waters so that the metal is fully coordinated by six amino acids in the inward-occluded state. As the inner gate opens, Q378 and the A53 carbonyl withdraw and are replaced by waters. The metal is then released into the cytoplasmic aqueous vestibule. To facilitate the return to the outward-open state, Q378 and N59 donate hydrogen bonds to negatively-charged D56 in the inward-occluded return conformation seen in our G45R structure. Finally, as the transporter returns to an outward-open state, it may bind a proton in preparation for metal-binding. For the inward-open metal-bound model for DraNramp, we altered the reported coordination from the Mn2+-bound ScaNramp relatively low-resolution (3.4 Å) crystal structure (PDB: 5M95) by adding two metal-coordinating waters, as well as switching the aspartate coordination to bidentate and the asparagine coordination to monodentate to be consistent with our G223W structure.