Gouaux.indd NS old.indd

catalyse the movement of small polar or charged molecules across the hydrophobic barrier of the membrane bilayer. A large class of these proteins, termed secondary transporters, use the discharge of an ionic gradient to power the ‘uphill’ translocation of solute molecules across membranes. By coupling solute movement to ion transport, secondary transporters are able to concentrate solutes across a membrane by a factor of 10 (ref. 2), and solute flux can occur 10 times faster than by simple passive diffusion. Secondary transporters are found in all species throughout the kingdoms of life. In humans, they participate in a range of physiological processes, from the uptake of nutrients in the intestine to the transport of Na and Cl in the kidney and the removal of neurotransmitters from the synaptic cleft. Secondary transporters are therefore the target of multiple therapeutic agents, including thiazide diuretics, which inhibit a Na/Cl symporter in the distal convoluted tubule of the kidney, and selective serotonin re-uptake inhibitors (antidepressants), which block the activity of the serotonin transporter. At the level of primary structure, analyses of amino-acid sequence suggest that there are more than 100 distinct families of secondary transporter, with more than 40 families identified in humans alone. With respect to biological function, these amino-acid sequences encode transporters that act on a range of substrates including elemental cations and anions, aromatic neurotransmitters, nutrients and diand tripeptides. Transport is usually driven by proton or sodium transmembrane gradients. In this Review, we focus on transporters that are coupled to sodium ions. We will discuss what recent crystallographic advances relating to sodium-coupled transporters can tell us about the coupling of substrates to ions, the conformational state of the transporter at different stages of the transport cycle, the mechanisms of transport inhibition, and how the substrate and ion pathway is alternately opened and closed — or gated — to maintain a tightly coupled transport mechanism.