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- PDB-6x18: GLP-1 peptide hormone bound to Glucagon-Like peptide-1 (GLP-1) Re... -
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Open data
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Basic information
Entry | Database: PDB / ID: 6x18 | ||||||||||||||||||
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Title | GLP-1 peptide hormone bound to Glucagon-Like peptide-1 (GLP-1) Receptor | ||||||||||||||||||
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![]() | MEMBRANE PROTEIN / G-coupled protein receptor / GPCR | ||||||||||||||||||
Function / homology | ![]() glucagon receptor binding / glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of execution phase of apoptosis / post-translational protein targeting to membrane, translocation / feeding behavior / response to psychosocial stress / regulation of heart contraction ...glucagon receptor binding / glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of execution phase of apoptosis / post-translational protein targeting to membrane, translocation / feeding behavior / response to psychosocial stress / regulation of heart contraction / positive regulation of calcium ion import / cellular response to glucagon stimulus / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / PKA activation in glucagon signalling / regulation of insulin secretion / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / intracellular transport / Synthesis, secretion, and deacylation of Ghrelin / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / positive regulation of gluconeogenesis / protein kinase A signaling / adenylate cyclase activator activity / negative regulation of blood pressure / cAMP-mediated signaling / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / response to activity / gluconeogenesis / G-protein beta/gamma-subunit complex binding / bone development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / hormone activity / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / platelet aggregation / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / transmembrane signaling receptor activity / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of peptidyl-serine phosphorylation / GTPase binding / retina development in camera-type eye / glucose homeostasis / Ca2+ pathway / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / secretory granule lumen / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade / learning or memory / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway Similarity search - Function | ||||||||||||||||||
Biological species | ![]() ![]() ![]() | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.1 Å | ||||||||||||||||||
![]() | Belousoff, M.J. / Zhang, X. / Danev, R. | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. Authors: Xin Zhang / Matthew J Belousoff / Peishen Zhao / Albert J Kooistra / Tin T Truong / Sheng Yu Ang / Christina Rye Underwood / Thomas Egebjerg / Petr Šenel / Gregory D Stewart / Yi-Lynn Liang ...Authors: Xin Zhang / Matthew J Belousoff / Peishen Zhao / Albert J Kooistra / Tin T Truong / Sheng Yu Ang / Christina Rye Underwood / Thomas Egebjerg / Petr Šenel / Gregory D Stewart / Yi-Lynn Liang / Alisa Glukhova / Hari Venugopal / Arthur Christopoulos / Sebastian G B Furness / Laurence J Miller / Steffen Reedtz-Runge / Christopher J Langmead / David E Gloriam / Radostin Danev / Patrick M Sexton / Denise Wootten / ![]() ![]() ![]() ![]() ![]() Abstract: Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. ...Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs. #1: ![]() Title: Differential GLP-1R binding and activation by peptide and non-peptide agonists Authors: Zhang, X. / Belousoff, M.J. / Zhao, P. / Ang, S.Y. / Truong, T.T. / Kooistra, A.J. / Underwood, C.R. / Egebjerg, T. / Stewart, G.D. / Liang, Y.L. / Glukhova, A. / Venugopal, H. / ...Authors: Zhang, X. / Belousoff, M.J. / Zhao, P. / Ang, S.Y. / Truong, T.T. / Kooistra, A.J. / Underwood, C.R. / Egebjerg, T. / Stewart, G.D. / Liang, Y.L. / Glukhova, A. / Venugopal, H. / Christopoulos, A. / Furness, S.G.B. / Miller, L.J. / Runge, S.R. / Gloriam, D.E. / Langmead, C.J. / Danev, R. / Sexton, P.M. / Wootten, D. | ||||||||||||||||||
History |
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Structure visualization
Movie |
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 255.9 KB | Display | ![]() |
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PDB format | ![]() | 205.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 21992MC ![]() 6x19C ![]() 6x1aC M: map data used to model this data C: citing same article ( |
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Similar structure data | |
EM raw data | ![]() Data size: 1.9 TB Data #1: Non-gain-normalized LZW-TIFF compressed movies of GLP-1R-GLP-1 in a detergent micelle [micrographs - multiframe]) |
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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: 45683.434 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#2: Protein | Mass: 37413.863 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#3: Protein | Mass: 6375.332 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Antibody / Protein/peptide / Protein / Non-polymers , 4 types, 101 molecules NPR![](data/chem/img/HOH.gif)
![](data/chem/img/HOH.gif)
#4: Antibody | Mass: 13885.439 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
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#5: Protein/peptide | Mass: 3302.648 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) ![]() |
#6: Protein | Mass: 56748.418 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#7: Water | ChemComp-HOH / |
-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 |
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Molecular weight | Value: 0.120 MDa / Experimental value: NO | ||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.4 | ||||||||||||||||||||||||
Specimen | Conc.: 3.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
Software | Name: PHENIX / Version: 1.16_3549: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 635785 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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