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Open data
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Basic information
Entry | Database: PDB / ID: 8wg8 | ||||||||||||||||||||||||
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Title | Cryo-EM structures of peptide free and Gs-coupled GCGR | ||||||||||||||||||||||||
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![]() | MEMBRANE PROTEIN / G protein-coupled receptor / ligand recognition / receptor activation / unimolecular agonist | ||||||||||||||||||||||||
Function / homology | ![]() regulation of glycogen metabolic process / glucagon receptor activity / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding ...regulation of glycogen metabolic process / glucagon receptor activity / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / alkylglycerophosphoethanolamine phosphodiesterase activity / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / cellular response to glucagon stimulus / exocytosis / response to starvation / peptide hormone binding / photoreceptor outer segment / cardiac muscle cell apoptotic process / cellular response to starvation / hormone-mediated signaling pathway / photoreceptor inner segment / response to nutrient / guanyl-nucleotide exchange factor activity / generation of precursor metabolites and energy / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / regulation of blood pressure / Glucagon-type ligand receptors / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / glucose homeostasis / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / cell body / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / cell surface receptor signaling pathway / endosome / G protein-coupled receptor signaling pathway / GTPase activity / dendrite / protein-containing complex binding / positive regulation of gene expression / membrane / plasma membrane / cytoplasm Similarity search - Function | ||||||||||||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() synthetic construct (others) ![]() ![]() | ||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.71 Å | ||||||||||||||||||||||||
![]() | Cong, Z.T. / Zhao, F.H. / Li, Y. / Luo, G. / Zhou, Q.T. / Yang, D.H. / Wang, M.W. | ||||||||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with G proteins. Authors: Zhaotong Cong / Fenghui Zhao / Yang Li / Gan Luo / Yiting Mai / Xianyue Chen / Yanyan Chen / Shi Lin / Xiaoqing Cai / Qingtong Zhou / Dehua Yang / Ming-Wei Wang / ![]() ![]() 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- ...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. | ||||||||||||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 197 KB | Display | ![]() |
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PDB format | ![]() | 150.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1 MB | Display | ![]() |
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Full document | ![]() | 1 MB | Display | |
Data in XML | ![]() | 38.3 KB | Display | |
Data in CIF | ![]() | 56.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 37505MC ![]() 8wa3C ![]() 8wg7C M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 41793.418 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Protein | Mass: 40226.992 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
-Antibody / Protein / Protein/peptide , 3 types, 3 molecules NRE
#4: Antibody | Mass: 15343.019 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: ![]() ![]() |
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#5: Protein | Mass: 46812.441 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#6: Protein/peptide | Mass: 1943.289 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Cryo-EM structure of the human glucagon like peptide 1 receptor in complex with tirzepatide and G protein Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.71 Å / Resolution method: OTHER / Num. of particles: 1232018 / Symmetry type: POINT | ||||||||||||||||||||||||
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