GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors

Sijie Huang, Peiyu Xu, Dan-Dan Shen, Icaro A Simon, Chunyou Mao, Yangxia Tan, Huibing Zhang, Kasper Harpsøe, Huadong Li, Yumu Zhang, Chongzhao You, Xuekui Yu, Yi Jiang, Yan Zhang, David E Gloriam*, H Eric Xu

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.

Original languageEnglish
JournalMolecular Cell
Volume82
Issue number14
Pages (from-to)2681-2695.e6
Number of pages15
ISSN1097-2765
DOIs
Publication statusPublished - 2022

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