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Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
Cong, Zhaotong; Chen, Li-Nan; Ma, Honglei; Zhou, Qingtong; Zou, Xinyu; Ye, Chenyu; Dai, Antao; Liu, Qing; Huang, Wei; Sun, Xianqiang; Wang, Xi; Xu, Peiyu; Zhao, Lihua; Xia, Tian; Zhong, Wenge; Yang, Dehua; Eric Xu, H; Zhang, Yan; Wang, Ming-Wei.
Affiliation
  • Cong Z; School of Pharmacy, Fudan University, Shanghai, China.
  • Chen LN; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Ma H; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Zhou Q; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Zou X; School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • Ye C; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, China.
  • Dai A; School of Pharmacy, Fudan University, Shanghai, China.
  • Liu Q; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Huang W; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Sun X; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Wang X; Qilu Regor Therapeutics, Inc., Shanghai, China.
  • Xu P; Qilu Regor Therapeutics, Inc., Shanghai, China.
  • Zhao L; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Xia T; University of Chinese Academy of Sciences, Beijing, China.
  • Zhong W; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Yang D; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Eric Xu H; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, China.
  • Zhang Y; Qilu Regor Therapeutics, Inc., Shanghai, China.
  • Wang MW; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
Nat Commun ; 12(1): 3763, 2021 06 18.
Article in En | MEDLINE | ID: mdl-34145245
The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Glucagon-Like Peptide 1 / Glucagon-Like Peptide-1 Receptor Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2021 Document type: Article Affiliation country: China Country of publication: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Glucagon-Like Peptide 1 / Glucagon-Like Peptide-1 Receptor Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2021 Document type: Article Affiliation country: China Country of publication: United kingdom