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

  • Science. 2020 Mar 20;367(6484):1346-1352. doi: 10.1126/science.aaz5346.
Anna Qiao  1  2  3 ,  Shuo Han  1  2 ,  Xinmei Li  3  4 ,  Zhixin Li  5 ,  Peishen Zhao  6 ,  Antao Dai  1  7 ,  Rulve Chang  5 ,  Linhua Tai  3  4 ,  Qiuxiang Tan  1  2 ,  Xiaojing Chu  1  2 ,  Limin Ma  1  2 ,  Thor Seneca Thorsen  8 ,  Steffen Reedtz-Runge  8 ,  Dehua Yang  1  7 ,  Ming-Wei Wang  1  3  5  7  9 ,  Patrick M Sexton  5  6 ,  Denise Wootten  10  6 ,  Fei Sun  11  4  12 ,  Qiang Zhao  13  3  14 ,  Beili Wu  15  3  9  14
Affiliations
  • 1. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4. National Laboratory of Biomacromolecules, National Center of Protein Science-Beijing, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 5. School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 6. Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
  • 7. National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 8. Novo Nordisk A/S, Måløv 2760, Denmark.
  • 9. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 10. School of Pharmacy, Fudan University, Shanghai 201203, China. [email protected] [email protected] [email protected] [email protected].
  • 11. University of Chinese Academy of Sciences, Beijing 100049, China. [email protected] [email protected] [email protected] [email protected].
  • 12. Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 13. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. [email protected] [email protected] [email protected] [email protected].
  • 14. CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China.
  • 15. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. [email protected] [email protected] [email protected] [email protected].
PMID: 32193322 DOI: 10.1126/science.aaz5346
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.