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GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors.
Huang, Sijie; Xu, Peiyu; Shen, Dan-Dan; Simon, Icaro A; Mao, Chunyou; Tan, Yangxia; Zhang, Huibing; Harpsøe, Kasper; Li, Huadong; Zhang, Yumu; You, Chongzhao; Yu, Xuekui; Jiang, Yi; Zhang, Yan; Gloriam, David E; Xu, H Eric.
Affiliation
  • Huang S; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Xu P; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Shen DD; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integra
  • Simon IA; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; SARomics Biostructures AB, Scheelevägen 2, 223 63 Lund, Sweden; Present address: Vrije Universiteit Amsterdam, Division of Medicinal Chemistry, Amsterdam Institute of Molecular and L
  • Mao C; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integra
  • Tan Y; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Zhang H; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integra
  • Harpsøe K; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
  • Li H; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Zhang Y; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • You C; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Yu X; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Jiang Y; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Zhang Y; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integra
  • Gloriam DE; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: david.gloriam@sund.ku.dk.
  • Xu HE; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic
Mol Cell ; 82(14): 2681-2695.e6, 2022 07 21.
Article in En | MEDLINE | ID: mdl-35714614
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Serotonin / Receptors, G-Protein-Coupled Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2022 Document type: Article Affiliation country: China Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Serotonin / Receptors, G-Protein-Coupled Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2022 Document type: Article Affiliation country: China Country of publication: United States