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Significance Membrane transport proteins are responsible for moving substrates, such as nutrients, vitamins, drugs, and signaling molecules across cellular membranes. A subset of these proteins, the ion-coupled transporters, use a transmembrane ion gradient to drive energetically unfavorable substrate movement from a lower concentration on one side of the membrane to a higher concentration on the other side. They do this by coupling the movement of substrate and ions in the same or the opposite direction. Coupled transport requires conformational changes that occur exclusively or predominantly when specific conditions of ion and substrate binding are met. This work identifies, for a family of Na+ -coupled neurotransmitter transporters, how the rules controlling these conformational changes are encoded in the transporter structure.

Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT