Structural basis of G s and G i recognition by the human glucagon receptor

• Published in: Science (American Association for the Advancement of Science) Vol. 367; no. 6484; pp. 1346 - 1352
• Main Authors: Qiao, Anna, Han, Shuo, Li, Xinmei, Li, Zhixin, Zhao, Peishen, Dai, Antao, Chang, Rulve, Tai, Linhua, Tan, Qiuxiang, Chu, Xiaojing, Ma, Limin, Thorsen, Thor Seneca, Reedtz-Runge, Steffen, Yang, Dehua, Wang, Ming-Wei, Sexton, Patrick M, Wootten, Denise, Sun, Fei, Zhao, Qiang, Wu, Beili
• Format: Journal Article
• Language: English
• Published: United States 20.03.2020
• Subjects: Binding Sites; Cryoelectron Microscopy; Glucagon - chemistry; Glucagon - metabolism; GTP-Binding Protein alpha Subunits, Gi-Go - chemistry; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gi-Go - ultrastructure; GTP-Binding Protein alpha Subunits, Gs - chemistry; GTP-Binding Protein alpha Subunits, Gs - metabolism; GTP-Binding Protein alpha Subunits, Gs - ultrastructure; Humans; Models, Molecular; Protein Binding; Protein Conformation; Protein Conformation, alpha-Helical; Receptors, Glucagon - chemistry; Receptors, Glucagon - metabolism; Receptors, Glucagon - ultrastructure; Signal Transduction
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaz5346

Class B G protein-coupled receptors, an important class of therapeutic targets, signal mainly through the G class of heterotrimeric G proteins, although they do display some promiscuity in G protein binding. Using cryo-electron microscopy, we determined the structures of the human glucagon receptor (GCGR) bound to glucagon and distinct classes of heterotrimeric G proteins, G or G These two structures adopt a similar open binding cavity to accommodate G and G The G binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect G more than G binding. Conformational differences in the receptor intracellular loops were found to be key selectivity determinants. These distinctions in transducer engagement were supported by mutagenesis and functional studies.