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Structural basis for the tethered peptide activation of adhesion GPCRs.
Ping, Yu-Qi; Xiao, Peng; Yang, Fan; Zhao, Ru-Jia; Guo, Sheng-Chao; Yan, Xu; Wu, Xiang; Zhang, Chao; Lu, Yan; Zhao, Fenghui; Zhou, Fulai; Xi, Yue-Tong; Yin, Wanchao; Liu, Feng-Zhen; He, Dong-Fang; Zhang, Dao-Lai; Zhu, Zhong-Liang; Jiang, Yi; Du, Lutao; Feng, Shi-Qing; Schöneberg, Torsten; Liebscher, Ines; Xu, H Eric; Sun, Jin-Peng.
Afiliación
  • Ping YQ; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Xiao P; CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Yang F; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Zhao RJ; Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Guo SC; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Yan X; Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Wu X; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Zhang C; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Lu Y; Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Zhao F; Advanced Medical Research Institute, Shandong University, Jinan, China.
  • Zhou F; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Xi YT; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Yin W; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Liu FZ; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • He DF; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Zhang DL; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Zhu ZL; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Jiang Y; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Du L; CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Feng SQ; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Schöneberg T; School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Liebscher I; CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Xu HE; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Sun JP; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Nature ; 604(7907): 763-770, 2022 04.
Article en En | MEDLINE | ID: mdl-35418678
Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes1-6. Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence7-12. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with Gs: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-ß-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W6.53 and the constitution of a hydrogen-bond network formed by Q7.49/Y7.49 and the P6.47/V6.47φφG6.50 motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and Gs coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common Gs-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with Gs. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their Gs coupling.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Receptores Acoplados a Proteínas G Idioma: En Revista: Nature Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Receptores Acoplados a Proteínas G Idioma: En Revista: Nature Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido