Structural basis of Gs and Gi recognition by the human glucagon receptor

Anna Qiao, Shuo Han, Xinmei Li, Zhixin Li, Peishen Zhao, Antao Dai, Rulve Chang, Linhua Tai, Qiuxiang Tan, Xiaojing Chu, Limin Ma, Thor Seneca Thorsen, Steffen Reedtz-Runge, Dehua Yang, Ming-Wei Wang, Patrick M. Sexton, Denise Wootten, Fei Sun, Qiang Zhao, Beili Wu

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6 Citations (Scopus)

Abstract

Class B G protein-coupled receptors, an important class of therapeutic targets, signal mainly through the Gs 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, Gs or Gi1. These two structures adopt a similar open binding cavity to accommodate Gs and Gi1. The Gs binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect Gi more than Gs 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.

Original languageEnglish
Pages (from-to)1346-1352
Number of pages7
JournalScience
Volume367
Issue number6484
DOIs
Publication statusPublished - 20 Mar 2020

Cite this

Qiao, A., Han, S., Li, X., Li, Z., Zhao, P., Dai, A., Chang, R., Tai, L., Tan, Q., Chu, X., Ma, L., Thorsen, T. S., Reedtz-Runge, S., Yang, D., Wang, M-W., Sexton, P. M., Wootten, D., Sun, F., Zhao, Q., & Wu, B. (2020). Structural basis of Gs and Gi recognition by the human glucagon receptor. Science, 367(6484), 1346-1352. https://doi.org/10.1126/science.aaz5346