Structural insights into constitutive activity of 5-HT6 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-HT6R-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-HT6R-Gs heterotrimer at 3.0-A resolution. Detailed analyses of the structure complemented by comprehensive interrogation of signaling illuminate key structural determinants essential for constitutive 5-HT6R activity. Additional structure-guided mutagenesis leads to a nanobody mimic Gas for 5-HT6R that can reduce its constitutive activity. Given the importance of 5-HT6R 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.

Automated summary

The cryo-EM structure of human 5-HT6R-Gs heterotrimer reveals key structural determinants for its constitutive activity, which can be targeted for the design of more effective medications for neuropsychiatric disorders. This study provides valuable insights into the molecular basis of constitutive activity and its therapeutic potential.