8wa3

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

spinqualitylabelsall models 8wa3, resolution 2.86Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8wa3 is a 5 chain structure with sequence from Bos taurus, Homo sapiens, Leptolinea tardivitalis, Rattus norvegicus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.86Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with G(s) proteins.,Cong Z, Zhao F, Li Y, Luo G, Mai Y, Chen X, Chen Y, Lin S, Cai X, Zhou Q, Yang D, Wang MW Cell Discov. 2024 Feb 13;10(1):18. doi: 10.1038/s41421-024-00649-0. PMID:38346960 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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