Structural Insights into Constitutive Activity of 5-HT 6 Receptor

While most therapeutic research on G-protein-coupled receptors (GPCRs) focuses on receptor activation by (endogenous) agonists, significant therapeutic potential exists through agonist-independent intrinsic constitutive activity that can occur in various physiological and pathophysiological settings. For example, inhibiting the constitutive activity of 5-HT 6 R—a receptor that is found almost exclusively in the brain and mediates excitatory neurotransmission—has demonstrated a therapeutic effect on cognitive/memory impairment associated with several neuropsychiatric disorders. However, the structural basis of such constitutive activity remains unclear. Here, we present a cryo-EM structure of serotonin-bound human 5-HT 6 R-Gs heterotrimer at 3.0-Å resolution. Detailed analyses of the structure complemented by comprehensive interrogation of signaling illuminate key structural determinants essential for constitutive 5-HT 6 R activity. Additional structure-guided mutagenesis leads to a nanobody mimic Gαs for 5-HT 6 R that can reduce its constitutive activity. Given the importance of 5-HT 6 R for a large number of neuropsychiatric disorders, insights derived from these studies will accelerate the design of more effective medications, and shed light on the molecular basis of constitutive activity.