Topic Overview:
Secondary active transporters harness the energy stored in electrochemical gradients to drive solutes across cell membranes. This task is accomplished by the alternating access mechanism, in which the transporter binds cargo from the outside of the cell membrane then undergoes a conformational change to release the cargo into the cell. 

Sodium-glucose cotransporters (SGLTs) are prototypes of secondary active transporters that drive the accumulation of sugars, amino acids, and other molecules into cells. In humans, these transporters play critical roles in the physiology of the brain, intestine, kidneys, and thyroid, and mutations in their genes are responsible for severe congenital diseases. Furthermore, SGLTs can be used as molecular targets for diabetes and obesity drugs.

Grabe will discuss his molecular simulation, X-ray crystallography, and functional experiments that have elucidated how transporters release sugar into the cell. With this work, Grabe’s group has proven one of the central tenets of the alternating access mechanism as first proposed in the 1960s―that substrate easily unbinds from the cell on the inward-facing state of the transporter. His simulation experiments also highlight the importance of SGLTs in water transport in the intestines, which has profound consequences for normal water homeostasis and for the treatment of severe dehydration.