Figure 11–9 Mechanism of glucose transport fueled by a Na+ gradient. As in the model shown in Figure 11–5,  the transporter alternates between inward-open and outward-open states via an occluded intermediate state. Binding of  Na+ and glucose is cooperative—that is, the binding of either solute increases the protein’s affinity for the other. Since the  Na+ concentration is much higher in the extracellular space than in the cytosol, glucose is more likely to bind to the transporter in the outward-facing state. The transition to the occluded state occurs only when both Na+ and glucose are bound; their precise interactions in the solute-binding sites slightly stabilize the occluded state and thereby make this transition energetically favorable. Stochastic fluctuations caused by thermal energy drive the transporter randomly into the inward-open or outward-open conformation. If it opens outwardly, nothing is achieved, and the process starts all over. However, whenever it opens inwardly, Na+ dissociates quickly in the low-Na+-concentration environment of the cytosol. Glucose dissociation is likewise enhanced when Na+ is lost, because of cooperativity in binding of the two solutes. The overall result is the net transport of  both Na+ and glucose into the cell. Because the occluded state is not formed when only one of the solutes is bound, the transporter switches conformation only when it is fully occupied or fully empty, thereby assuring strict coupling of the transport of Na+ and glucose.
into the cell (Figure 11–9). Neurotransmitters (released by nerve cells to signal at synapses—as we discuss later) are taken up again by Na+ symporters after their release. These neurotransmitter transporters are important drug targets: stimulants, such as cocaine and antidepressants, inhibit them and thereby prolong signaling by the neurotransmitters, which are not cleared efficiently.
Despite their great variety, transporters share structural features that can explain how they function and how they evolved. Transporters are typically built from bundles of 10 or more α helices that span the membrane. Soluteand ion-binding sites are located midway through the membrane, where some helices are broken or distorted and amino acid side chains and polypeptide backbone atoms form ionand solute-binding sites. In the inward-open and outward-open conformations, these binding sites are accessible by passageways from one side of the membrane but not the other. In switching between the two conformations, the transporter protein transiently adopts an occluded conformation, in which both passageways are closed; this prevents the driving ion and the transported solute from crossing the membrane unaccompanied, which would deplete the cell’s energy store to no purpose. Because only transporters with both types of binding sites appropriately filled change their conformation, tight coupling between ion and solute transport is assured.
Like enzymes, transporters can work in the reverse direction if ion and solute gradients are appropriately adjusted experimentally. This chemical symmetry is mirrored in their physical structure. Crystallographic analyses have revealed that transporters are built from inverted repeats: the packing of the transmembrane α helices in one half of the helix bundle is structurally similar to the packing in the other half, but the two halves are inverted in the membrane relative to each other. Transporters are therefore said to be pseudosymmetric, and the passageways that open and close on either side of the membrane have closely similar geometries, allowing alternating access to the ionand solute-binding sites in the center (Figure 11–10). It is thought that the two halves evolved by gene duplication of a smaller ancestor protein.