Workshop 8 - CNS drug discovery and development

Question 1

How is the structure of SERT related to receptor binding?

Answer 1

SERT undergoes conformational changes.

1. Outward open conformation - the trasnsporter has a large hydrophobic cavity which acts to direct seratonin and other lipophillic small molecules towards the active site. It does this by recruiting a Na ion to the active site, followed by seratonin and then a chloride ion. The binding of a negatively charged chloride ion alters the membrane potential allowing SERT to flip to its inward open conformation. This can then deposit seratonin, Na and Cl ion into the cytoplasm. SERT then recruits a K ion to the active site reversing its membrane potential resulting in a flip back to the outward open conformation. The K ion is then released to the extracellular fluids and the cycle can repeat.