Structural insights into constitutive activity of 5-HT 6 receptor

作者：Licong He, Qiaoyu Zhao, Jianzhong Qi, Yifan Wang, Wenyu Han, Zhangcheng Chen, Yao Cong, Sheng Wang · 发表于：Proceedings of the National Academy of Sciences · 年份：2023 · DOI：10.1073/pnas.2209917120 · 被引用次数：11 · 研究领域：Receptor Mechanisms and Signaling、Neurotransmitter Receptor Influence on Behavior、Neuroscience and Neuropharmacology Research

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.