Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

Yan Zhang, Bingfa Sun, Dan Feng, Hongli Hu, Matthew Chu, Qianhui Qu, Jeffrey T. Tarrasch, Shane Li, Tong Sun Kobilka, Brian K. Kobilka () and Georgios Skiniotis ()
Additional contact information
Yan Zhang: University of Michigan Medical School
Bingfa Sun: ConfometRx
Dan Feng: ConfometRx
Hongli Hu: University of Michigan Medical School
Matthew Chu: ConfometRx
Qianhui Qu: University of Michigan Medical School
Jeffrey T. Tarrasch: University of Michigan Medical School
Shane Li: ConfometRx
Tong Sun Kobilka: ConfometRx
Brian K. Kobilka: ConfometRx
Georgios Skiniotis: University of Michigan Medical School

Nature, 2017, vol. 546, issue 7657, 248-253

Abstract: Abstract Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1R–Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5-helix of the Ras-like domain of Gs. These results provide a structural framework for understanding class B GPCR activation through hormone binding.

Date: 2017
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DOI: 10.1038/nature22394

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