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Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide.
Chang, Rulue; Zhang, Xin; Qiao, Anna; Dai, Antao; Belousoff, Matthew J; Tan, Qiuxiang; Shao, Lijun; Zhong, Li; Lin, Guangyao; Liang, Yi-Lynn; Ma, Limin; Han, Shuo; Yang, Dehua; Danev, Radostin; Wang, Ming-Wei; Wootten, Denise; Wu, Beili; Sexton, Patrick M.
Afiliação
  • Chang R; School of Pharmacy, Shanghai Medical College, Fudan University, Shanghai, China.
  • Zhang X; Monash Institute of Pharmaceutical Sciences, Drug Discovery Biology, Monash University, Parkville, Victoria, Australia.
  • Qiao A; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Dai A; University of Chinese Academy of Sciences, Beijing, China.
  • Belousoff MJ; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Tan Q; The National Center for Drug Screening, Shanghai, China.
  • Shao L; Monash Institute of Pharmaceutical Sciences, Drug Discovery Biology, Monash University, Parkville, Victoria, Australia.
  • Zhong L; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Lin G; University of Chinese Academy of Sciences, Beijing, China.
  • Liang YL; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Ma L; University of Chinese Academy of Sciences, Beijing, China.
  • Han S; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Yang D; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Danev R; University of Chinese Academy of Sciences, Beijing, China.
  • Wang MW; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Wootten D; University of Chinese Academy of Sciences, Beijing, China.
  • Wu B; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • Sexton PM; Monash Institute of Pharmaceutical Sciences, Drug Discovery Biology, Monash University, Parkville, Victoria, Australia.
J Biol Chem ; 295(28): 9313-9325, 2020 07 10.
Article em En | MEDLINE | ID: mdl-32371397
Unimolecular dual agonists of the glucagon (GCG) receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) are a new class of drugs that are potentially superior to GLP-1R-specific agonists for the management of metabolic disease. The dual-agonist, peptide 15 (P15), is a glutamic acid 16 analog of GCG with GLP-1 peptide substitutions between amino acids 17 and 24 that has potency equivalent to those of the cognate peptide agonists at the GCGR and GLP-1R. Here, we have used cryo-EM to solve the structure of an active P15-GCGR-Gs complex and compared this structure to our recently published structure of the GCGR-Gs complex bound to GCG. This comparison revealed that P15 has a reduced interaction with the first extracellular loop (ECL1) and the top of transmembrane segment 1 (TM1) such that there is increased mobility of the GCGR extracellular domain and at the C terminus of the peptide compared with the GCG-bound receptor. We also observed a distinct conformation of ECL3 and could infer increased mobility of the far N-terminal His-1 residue in the P15-bound structure. These regions of conformational variance in the two peptide-bound GCGR structures were also regions that were distinct between GCGR structures and previously published peptide-bound structures of the GLP-1R, suggesting that greater conformational dynamics may contribute to the increased efficacy of P15 in activation of the GLP-1R compared with GCG. The variable domains in this receptor have previously been implicated in biased agonism at the GLP-1R and could result in altered signaling of P15 at the GCGR compared with GCG.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos / Receptores de Glucagon / Microscopia Crioeletrônica Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos / Receptores de Glucagon / Microscopia Crioeletrônica Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China