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Yorodumi- PDB-6orv: Non-peptide agonist (TT-OAD2) bound to the Glucagon-Like peptide-... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6orv | ||||||||||||||||||
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Title | Non-peptide agonist (TT-OAD2) bound to the Glucagon-Like peptide-1 (GLP-1) Receptor | ||||||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / G-coupled protein receptor / GPCR / non-peptide angonist | ||||||||||||||||||
Function / homology | Function and homology information glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / regulation of heart contraction / response to psychosocial stress / PKA activation in glucagon signalling / peptide hormone binding / cAMP-mediated signaling ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / regulation of heart contraction / response to psychosocial stress / PKA activation in glucagon signalling / peptide hormone binding / cAMP-mediated signaling / hair follicle placode formation / intracellular transport / D1 dopamine receptor binding / developmental growth / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / trans-Golgi network membrane / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / Glucagon-type ligand receptors / cognition / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / transmembrane signaling receptor activity / signaling receptor complex adaptor activity / sensory perception of smell / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / learning or memory / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | ||||||||||||||||||
Authors | Belousoff, M.J. / Liang, Y.L. / Danev, R. | ||||||||||||||||||
Funding support | Australia, 5items
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Citation | Journal: Nature / Year: 2020 Title: Activation of the GLP-1 receptor by a non-peptidic agonist. Authors: Peishen Zhao / Yi-Lynn Liang / Matthew J Belousoff / Giuseppe Deganutti / Madeleine M Fletcher / Francis S Willard / Michael G Bell / Michael E Christe / Kyle W Sloop / Asuka Inoue / Tin T ...Authors: Peishen Zhao / Yi-Lynn Liang / Matthew J Belousoff / Giuseppe Deganutti / Madeleine M Fletcher / Francis S Willard / Michael G Bell / Michael E Christe / Kyle W Sloop / Asuka Inoue / Tin T Truong / Lachlan Clydesdale / Sebastian G B Furness / Arthur Christopoulos / Ming-Wei Wang / Laurence J Miller / Christopher A Reynolds / Radostin Danev / Patrick M Sexton / Denise Wootten / Abstract: Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity. Structures of active receptors reveal peptide agonists engage deep within ...Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity. Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation. Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors. | ||||||||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6orv.cif.gz | 196.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6orv.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 6orv.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/or/6orv ftp://data.pdbj.org/pub/pdb/validation_reports/or/6orv | HTTPS FTP |
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-Related structure data
Related structure data | 20179MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10346 (Title: Cryo-EM of GLP-1 receptor bound to TT-OAD2 non-peptidic agonist Data size: 6.2 TB Data #1: Unaligned multi-frame movies of GLP-1R-TT-OAD2 complex [micrographs - multiframe] Data #2: Unaligned multi-frame movies of GLP-1R-TT-OAD2 complex [micrographs - multiframe]) |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules APBPGP
#1: Protein | Mass: 45683.434 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63092 |
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#2: Protein | Mass: 38534.062 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873 |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768 |
-Antibody / Protein / Non-polymers , 3 types, 3 molecules NPRP
#4: Antibody | Mass: 15140.742 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) |
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#5: Protein | Mass: 56748.418 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GLP1R / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P43220 |
#6: Chemical | ChemComp-N2V / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-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 | ||||||||||||||||||||||||
Specimen support | Grid material: COPPER / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
-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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy |
Image recording | Electron dose: 66.65 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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Symmetry | Point symmetry: C1 (asymmetric) |
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85978 / Symmetry type: POINT |