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Yorodumi- PDB-6vcb: Cryo-EM structure of the Glucagon-like peptide-1 receptor in comp... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6vcb | ||||||
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Title | Cryo-EM structure of the Glucagon-like peptide-1 receptor in complex with G protein, GLP-1 peptide and a positive allosteric modulator | ||||||
Components |
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Keywords | SIGNALING PROTEIN/MEMBRANE PROTEIN / G protein-coupled receptor / membrane protein / family B GPCR / diabetes / allosteric modulator / SIGNALING PROTEIN-MEMBRANE PROTEIN complex | ||||||
Function / homology | Function and homology information 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 / regulation of heart contraction / activation of adenylate cyclase activity ...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 / regulation of heart contraction / activation of adenylate cyclase activity / response to psychosocial stress / positive regulation of calcium ion import / cellular response to glucagon stimulus / positive regulation of insulin secretion involved in cellular response to glucose stimulus / regulation of insulin secretion / peptide hormone binding / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of gluconeogenesis / cAMP-mediated signaling / protein kinase A signaling / negative regulation of blood pressure / positive regulation of peptidyl-threonine phosphorylation / response to activity / gluconeogenesis / adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / hormone activity / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / transmembrane signaling receptor activity / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of peptidyl-serine phosphorylation / GTPase binding / glucose homeostasis / retina development in camera-type eye / Ca2+ pathway / 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 / endoplasmic reticulum lumen / lysosomal membrane / signaling receptor binding / GTPase activity / synapse / protein-containing complex binding / negative regulation of apoptotic process / signal transduction / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Lama glama (llama) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||
Authors | Sun, B. / Feng, D. / Bueno, A. / Kobilka, B. / Sloop, K. | ||||||
Citation | Journal: Nat Chem Biol / Year: 2020 Title: Structural insights into probe-dependent positive allosterism of the GLP-1 receptor. Authors: Ana B Bueno / Bingfa Sun / Francis S Willard / Dan Feng / Joseph D Ho / David B Wainscott / Aaron D Showalter / Michal Vieth / Qi Chen / Cynthia Stutsman / Betty Chau / James Ficorilli / ...Authors: Ana B Bueno / Bingfa Sun / Francis S Willard / Dan Feng / Joseph D Ho / David B Wainscott / Aaron D Showalter / Michal Vieth / Qi Chen / Cynthia Stutsman / Betty Chau / James Ficorilli / Francisco J Agejas / Graham R Cumming / Alma Jiménez / Isabel Rojo / Tong Sun Kobilka / Brian K Kobilka / Kyle W Sloop / Abstract: Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state ...Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric G. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein-protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone 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 | 6vcb.cif.gz | 225.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6vcb.ent.gz | 172 KB | Display | PDB format |
PDBx/mmJSON format | 6vcb.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6vcb_validation.pdf.gz | 918.1 KB | Display | wwPDB validaton report |
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Full document | 6vcb_full_validation.pdf.gz | 927.4 KB | Display | |
Data in XML | 6vcb_validation.xml.gz | 36.4 KB | Display | |
Data in CIF | 6vcb_validation.cif.gz | 55.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/vc/6vcb ftp://data.pdbj.org/pub/pdb/validation_reports/vc/6vcb | HTTPS FTP |
-Related structure data
Related structure data | 21147MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Glucagon-like peptide ... , 2 types, 2 molecules RP
#1: Protein | Mass: 51233.109 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P43220 |
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#2: Protein/peptide | Mass: 3359.699 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01275 |
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#3: Protein | Mass: 44326.160 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63092 |
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#4: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873 |
#5: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768 |
-Antibody / Non-polymers , 2 types, 2 molecules N
#6: Antibody | Mass: 17352.498 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli) |
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#7: Chemical | ChemComp-QW7 / |
-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: 0.15 MDa / Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||
Specimen | Conc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil, UltrAuFoil, R1.2/1.3 | ||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293 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: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Cs: 2.7 mm |
Image recording | Average exposure time: 10.8 sec. / Electron dose: 81.56 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
EM imaging optics | Energyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV |
Image scans | Movie frames/image: 54 |
-Processing
Software |
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EM software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 323427 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | B value: 72.5 / Protocol: FLEXIBLE FIT | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 5VAI | ||||||||||||||||||||||||
Refinement | Stereochemistry target values: GeoStd + Monomer Library | ||||||||||||||||||||||||
Refine LS restraints |
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