Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins PMID: 38346960

RQC and Longevity Regulation

2026-09-03

Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins

Cell Discov. 2024 Feb 13;10(1):18. doi: 10.1038/s41421-024-00649-0.

Zhaotong Cong ^# ¹ , Fenghui Zhao ^# ² ³ , Yang Li ⁴ , Gan Luo ⁵ , Yiting Mai ⁶ , Xianyue Chen ⁶ , Yanyan Chen ⁶ , Shi Lin ⁶ , Xiaoqing Cai ² ³ , Qingtong Zhou ⁷ ⁸ , Dehua Yang ⁹ ¹⁰ ¹¹ , Ming-Wei Wang ¹² ¹³ ¹⁴

Affiliations

1. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
2. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
3. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
4. Shanghai Institute of Infectious Disease and Biosecurity, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
5. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai, China.
6. Research Center for Deepsea Bioresources, Sanya, Hainan, China.
7. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
8. Research Center for Deepsea Bioresources, Sanya, Hainan, China. [email protected].
9. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
10. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
11. Research Center for Deepsea Bioresources, Sanya, Hainan, China. [email protected].
12. Research Center for Deepsea Bioresources, Sanya, Hainan, China. [email protected].
13. Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan. [email protected].
14. School of Pharmacy, Hainan Medical University, Haikou, Hainan, China. [email protected].
# Contributed equally.

Abstract

Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide Hormones, i.e., glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP). They trigger a cascade of signaling events leading to the formation of an active agonist-receptor-G protein complex. However, intracellular signal transducers can also activate the receptor independent of extracellular stimuli, suggesting an intrinsic role of G proteins in this process. Here, we report cryo-electron microscopy structures of the human GLP-1 Receptor (GLP-1R), GCG receptor (GCGR), and GIP receptor (GIPR) in complex with G_s proteins without the presence of cognate ligands. These ligand-free complexes share a similar intracellular architecture to those bound by endogenous Peptides, in which, the G_s protein alone directly opens the intracellular binding cavity and rewires the extracellular orthosteric pocket to stabilize the receptor in a state unseen before. While the peptide-binding site is partially occupied by the inward folded transmembrane helix 6 (TM6)-extracellular loop 3 (ECL3) juncture of GIPR or a segment of GCGR ECL2, the extracellular portion of GLP-1R adopts a conformation close to the active state. Our findings offer valuable insights into the distinct activation mechanisms of these three important receptors. It is possible that in the absence of a ligand, the intracellular half of transmembrane domain is mobilized with the help of G_s protein, which in turn rearranges the extracellular half to form a transitional conformation, facilitating the entry of the peptide N-terminus.