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

Article

关键词: PEPTIDE-1 RECEPTOR;    GLUCAGON RECEPTOR;    CRYSTAL-STRUCTURE;    EXTRACELLULAR LOOP;    COUPLED RECEPTORS;    DYNAMIC PROCESS;    BINDING;    FAMILY;    DOMAIN;    VISUALIZATION;   

DOI  :  10.1038/nature22394

来源: SCIE

【 摘 要 】

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 G(s). 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-G(s) 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 alpha 5-helix of the Ras-like domain of G(s). These results provide a structural framework for understanding class B GPCR activation through hormone binding.

【 授权许可】

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