Serotonin transporter allosteric S2 site (SERT S2 site)

The allosteric S2 site of the serotonin transporter (SERT) is a secondary binding pocket located within the extracellular vestibule of the transporter, positioned approximately 11-15 Å above the central orthosteric (S1) binding site (NIH, 2020; Stony Brook University, 2024). While the S1 site is the primary target for serotonin and most selective serotonin reuptake inhibitors (SSRIs), the S2 site plays a critical regulatory role by allosterically modulating the affinity and dissociation kinetics of ligands bound at the S1 site (PNAS, 2023; RSC, 2016). For instance, the antidepressant escitalopram binds to both the S1 and S2 sites; its occupancy of the S2 site slows its own dissociation from the S1 site, leading to a more potent and sustained inhibition of serotonin reuptake compared to other SSRIs (NIH, 2007; NIH, 2020). Conversely, the R-enantiomer of citalopram can also bind to the S2 site but acts to interfere with the allosteric stabilization of escitalopram, which may explain the superior clinical efficacy of pure escitalopram over the racemic mixture (NIH, 2007; NIH, 2016). Research into high-affinity allosteric modulators of SERT, such as Lu AF60097, aims to develop novel therapeutics that can more precisely tune serotonergic signaling with potentially fewer side effects than traditional orthosteric inhibitors (PNAS, 2023; Nature Communications, 2020).

Other names

S2 siteSecondary binding siteVestibular binding siteAllosteric binding site of SERTExtracellular vestibule site

Allosteric modulation of the serotonin transporter (SERT) by binding to the S2 site, which typically slows the dissociation of ligands from the orthosteric S1 site, thereby enhancing or prolonging reuptake inhibition.