Sodium-dependent serotonin transporter allosteric S2 site (SERT S2 site)

The Sodium-dependent serotonin transporter (SERT) allosteric S2 site is a secondary binding pocket located in the extracellular vestibule of the SERT protein, distinct from the primary orthosteric (S1) binding site (Chen et al., 2005, J. Biol. Chem.). Binding of specific ligands, most notably escitalopram, to this S2 site induces a conformational change that sterically hinders the dissociation of the ligand bound at the S1 site (Zhong et al., 2012, Nature). This allosteric mechanism enhances the potency and duration of serotonin reuptake inhibition compared to drugs that only occupy the S1 site (Plenge et al., 2007, Eur. Neuropsychopharmacol.). SERT is the primary target for treating major depressive disorder and anxiety, as it regulates the concentration of serotonin in the synaptic cleft (Stahl, 2013, Stahl's Essential Psychopharmacology). By modulating the kinetics of the transporter, drugs targeting the S2 site can achieve more sustained therapeutic effects. Understanding the S2 site has been crucial in the development of allosteric SSRIs which offer distinct pharmacological profiles (Sanchez et al., 2004, Psychopharmacology).

Other names

S2 allosteric siteSecondary binding site of SERTAllosteric site of SLC6A4Extracellular vestibule allosteric site

Allosteric modulation of the orthosteric site (S1) to stabilize drug binding and prolong the inhibition of serotonin reuptake.