The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) has resulted in an 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.
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Structural basis of Gs and Gi recognition by the human glucagon receptor, Science, 20 Mar 2020
Science, 20 Mar, 2020, DOI：https://doi.org/10.1126/science.aaz5346
Structural basis of Gs and Gi recognition by the human glucagon receptor
Anna Qiao, Shuo Han, Xinmei Li, Zhixin Li, Peishen Zhao, Antao Dai1, 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
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) has resulted in an 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.
文章链接：https://science.sciencemag.org/content/367/6484/1346