Nature Research, Nature Structural and Molecular Biology, 11(21), p. 1006-1012, 2014
DOI: 10.1038/nsmb.2894
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Neurotransmitter:sodium symporters (NSS) terminate synaptic signal transmission by Na+-dependent reuptake of released neurotransmitters, with key conformational states reported for a bacterial homolog LeuT and an inhibitor-bound Drosophila dopamine transporter. However, a coherent mechanism of Na+-driven transport has not been described. Here, we present two crystal structures of MhsT, a NSS member from Bacillus halodurans, in occluded inward-facing states with bound Na+ ions and L-Trp that provide insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, which is facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na2 site. Based on our structural and functional findings we propose a mechanism according to which solvation through the TM5 pathway facilitates Na+ release from Na2 and the transition to an inward-open state.