ジャーナル: Proc Natl Acad Sci U S A / 年: 2023 タイトル: Structural insights into constitutive activity of 5-HT receptor. 著者: Licong He / Qiaoyu Zhao / Jianzhong Qi / Yifan Wang / Wenyu Han / Zhangcheng Chen / Yao Cong / Sheng Wang / 要旨: While most therapeutic research on G-protein-coupled receptors (GPCRs) focuses on receptor activation by (endogenous) agonists, significant therapeutic potential exists through agonist-independent ...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-HTR-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-HTR-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-HTR activity. Additional structure-guided mutagenesis leads to a nanobody mimic Gαs for 5-HTR that can reduce its constitutive activity. Given the importance of 5-HTR 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.
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