8WA3

Cryo-EM structure of peptide free and Gs-coupled GIPR

Summary for 8WA3

• Entry DOI: 10.2210/pdb8wa3/pdb
• EMDB information: 37390
• Descriptor: Gastric inhibitory polypeptide receptor,Fusion protein, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,O-antigen polymerase, ... (5 entities in total)
• Functional Keywords: glucose-dependent insulinotropic polypeptide receptor; cryo-electron microscopy; g protein-coupled receptor; ligand recognition, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 174125.29

Authors

Cong, Z.T.,Zhao, F.H.,Li, Y.,Luo, G.,Zhou, Q.T.,Yang, D.H.,Wang, M.W. (deposition date: 2023-09-06, release date: 2024-03-06, Last modification date: 2025-04-23)

Primary citation

Cong, Z.,Zhao, F.,Li, Y.,Luo, G.,Mai, Y.,Chen, X.,Chen, Y.,Lin, S.,Cai, X.,Zhou, Q.,Yang, D.,Wang, M.W.
Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with G s proteins.
Cell Discov, 10:18-18, 2024

PubMed 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 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 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 protein, which in turn rearranges the extracellular half to form a transitional conformation, facilitating the entry of the peptide N-terminus.

PubMed: 38346960
DOI: 10.1038/s41421-024-00649-0

Experimental method

ELECTRON MICROSCOPY (2.86 Å)