+Open data
-Basic information
Entry | Database: PDB / ID: 7.0E+14 | ||||||
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Title | Compound2_GLP-1R_OWL833_Gs complex structure | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / ago-allosteric modulation of GLP-1R | ||||||
Function / homology | Function and homology information glucagon-like peptide 1 receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / glucagon receptor activity / hormone secretion / Activation of the phototransduction cascade / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / Activation of G protein gated Potassium channels ...glucagon-like peptide 1 receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / glucagon receptor activity / hormone secretion / Activation of the phototransduction cascade / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / 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 / 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 / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of heart contraction / Vasopressin regulates renal water homeostasis via Aquaporins / activation of adenylate cyclase activity / response to psychosocial stress / peptide hormone binding / negative regulation of blood pressure / cAMP-mediated signaling / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon-type ligand receptors / photoreceptor disc membrane / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / transmembrane signaling receptor activity / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / learning or memory / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / membrane / plasma membrane / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Bos taurus (cattle) Rattus norvegicus (Norway rat) synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å | ||||||
Authors | Cong, Z.T. / Chen, L.N. / Ma, H.L. / Yang, D.H. / Xu, H.E. / Zhang, Y. / Wang, M.W. | ||||||
Citation | Journal: Nat Commun / Year: 2021 Title: Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. Authors: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong ...Authors: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang / Abstract: The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy ...The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics. | ||||||
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 | 7e14.cif.gz | 217.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7e14.ent.gz | 168.1 KB | Display | PDB format |
PDBx/mmJSON format | 7e14.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7e14_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 7e14_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 7e14_validation.xml.gz | 40.4 KB | Display | |
Data in CIF | 7e14_validation.cif.gz | 60.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/e1/7e14 ftp://data.pdbj.org/pub/pdb/validation_reports/e1/7e14 | HTTPS FTP |
-Related structure data
Related structure data | 30936MC 7duqC 7durC 7evmC 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
-Protein , 5 types, 5 molecules ABGNR
#1: Protein | Mass: 28989.904 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) Production host: Insect cell expression vector pTIE1 (others) |
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#2: Protein | Mass: 37915.496 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Bos taurus (cattle) / Gene: GNB1 Production host: Insect cell expression vector pTIE1 (others) References: UniProt: P62871 |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) Production host: Insect cell expression vector pTIE1 (others) |
#4: Protein | Mass: 13885.439 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) Production host: Insect cell expression vector pTIE1 (others) |
#5: Protein | Mass: 50860.801 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GLP1R Production host: Insect cell expression vector pTIE1 (others) References: UniProt: P43220 |
-Non-polymers , 3 types, 7 molecules
#6: Chemical | ChemComp-V6G / | ||
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#7: Chemical | ChemComp-CLR / #8: Chemical | ChemComp-HNO / | |
-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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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 | ||||||||||||||||||||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-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: OTHER |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 345411 / Symmetry type: POINT |