Serotonin transporter and dopamine transporter S2 allosteric site (SERT/DAT S2 site)

The S2 allosteric site is a distinct binding pocket located within the extracellular vestibule of the serotonin transporter (SERT) and dopamine transporter (DAT), both members of the solute carrier 6 (SLC6) family [1][2]. While the primary S1 site is responsible for substrate binding and translocation, the S2 site acts as a regulatory domain that can allosterically influence the affinity and dissociation kinetics of ligands at the S1 site [3]. In SERT, the antidepressant escitalopram is known to bind to the S2 site, which stabilizes the drug-transporter complex at the primary site and enhances its inhibitory potency [1][4]. For DAT, the S2 site represents a potential target for developing atypical inhibitors that could treat ADHD or cocaine addiction by modulating dopamine reuptake without inducing the rapid surges associated with traditional stimulants [2]. Understanding the structural biology of the S2 site is crucial for the design of next-generation psychotropic medications that offer improved efficacy and safety profiles through fine-tuned allosteric modulation [3]. Sources: [1] Plenge et al. (2012) J Biol Chem; [2] Chen et al. (2013) J Biol Chem; [3] Niello et al. (2020) Front Physiol; [4] Zhong et al. (2015) Nature.

Other names

S2 binding siteAllosteric vestibule siteSecondary substrate binding siteLow-affinity allosteric siteSLC6 allosteric pocket

Allosteric modulation of the primary (S1) binding site, typically by slowing the dissociation rate of orthosteric ligands or inhibiting the conformational transition required for substrate translocation.