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Yorodumi- EMDB-30866: Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 r... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-30866 | |||||||||
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Title | Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 receptor-Gs complex | |||||||||
Map data | ||||||||||
Sample |
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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 / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor ...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 / 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 / post-translational protein targeting to membrane, translocation / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / feeding behavior / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / 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 / alkylglycerophosphoethanolamine phosphodiesterase activity / 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 / response to psychosocial stress / G alpha (i) signalling events / regulation of heart contraction / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of calcium ion import / cellular response to glucagon stimulus / response to starvation / 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 / photoreceptor outer segment / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Synthesis, secretion, and deacylation of Ghrelin / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of gluconeogenesis / cardiac muscle cell apoptotic process / protein kinase A signaling / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / photoreceptor inner segment / cAMP-mediated signaling / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / response to activity / gluconeogenesis / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cognition / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / platelet aggregation / Glucagon-type ligand receptors Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / synthetic construct (others) / Rattus norvegicus (Norway rat) / Bos taurus (cattle) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.5 Å | |||||||||
Authors | Cong Z / Chen L / Ma H / Zhou Q / Zou X / Ye C / Dai A / Liu Q / Huang W / Sun X ...Cong Z / Chen L / Ma H / Zhou Q / Zou X / Ye C / Dai A / Liu Q / Huang W / Sun X / Wang X / Xu P / Zhao L / Xia T / Zhong W / Yang D / Xu HE / Zhang Y / Wang M | |||||||||
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 | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_30866.map.gz | 40.1 MB | EMDB map data format | |
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Header (meta data) | emd-30866-v30.xml emd-30866.xml | 19 KB 19 KB | Display Display | EMDB header |
Images | emd_30866.png | 126 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-30866 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-30866 | HTTPS FTP |
-Validation report
Summary document | emd_30866_validation.pdf.gz | 464.9 KB | Display | EMDB validaton report |
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Full document | emd_30866_full_validation.pdf.gz | 464.5 KB | Display | |
Data in XML | emd_30866_validation.xml.gz | 5.8 KB | Display | |
Data in CIF | emd_30866_validation.cif.gz | 6.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30866 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30866 | HTTPS FTP |
-Related structure data
Related structure data | 7duqMC 7durC 7e14C 7evmC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_30866.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.045 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
+Entire : Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 r...
+Supramolecule #1: Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 r...
+Supramolecule #2: Guanine nucleotide-binding protein
+Supramolecule #3: Nanobody-35
+Supramolecule #4: Glucagon-like peptide 1 receptor
+Supramolecule #5: Glucagon-like peptide 1
+Macromolecule #1: Glucagon-like peptide 1
+Macromolecule #2: Glucagon-like peptide 1 receptor
+Macromolecule #3: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #6: Nanobody-35
+Macromolecule #7: N-tert-butyl-6,7-bis(chloranyl)quinoxalin-2-amine
+Macromolecule #8: CHOLESTEROL
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Average electron dose: 80.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: EMDB MAP EMDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 614978 |
Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |