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Structural insights into constitutive activity of 5-HT 6 receptor

Proceedings of the National Academy of Sciences - PNAS, 2023-04, Vol.120 (14), p.e2209917120 [Peer Reviewed Journal]

ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.2209917120 ;PMID: 36989299

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  • Title:
    Structural insights into constitutive activity of 5-HT 6 receptor
  • Author: He, Licong ; Zhao, Qiaoyu ; Qi, Jianzhong ; Wang, Yifan ; Han, Wenyu ; Chen, Zhangcheng ; Cong, Yao ; Wang, Sheng
  • Subjects: Brain - metabolism ; Humans ; Receptors, Serotonin - metabolism ; Serotonin ; Signal Transduction
  • Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2023-04, Vol.120 (14), p.e2209917120
  • Description: 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 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 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 R activity. Additional structure-guided mutagenesis leads to a nanobody mimic Gαs for 5-HT R that can reduce its constitutive activity. Given the importance of 5-HT 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.
  • Publisher: United States
  • Language: English
  • Identifier: ISSN: 0027-8424
    EISSN: 1091-6490
    DOI: 10.1073/pnas.2209917120
    PMID: 36989299
  • Source: GFMER Free Medical Journals
    MEDLINE
    PubMed Central
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