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Significance The combination of molecular dynamics simulation, single-molecule imaging, and functional assays described here reveals a mechanism of substrate selectivity in the SLC6 family of neurotransmitter transporters. We show that the rotameric state of a volumetric sensor in the substrate binding site is allosterically coupled to conformational changes necessary for transport, and as a consequence, upon binding large substrates, the transporter becomes stabilized in an inactive, nontransporting state upon binding larger substrates. This mechanistic insight suggests the possibility that medically relevant SLC6 transporters may be targeted by inhibitors that specifically modulate this sensor.

The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor