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- EMDB-21992: 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: EMDB / ID: EMD-21992 | ||||||||||||||||||
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Title | GLP-1 peptide hormone bound to Glucagon-Like peptide-1 (GLP-1) Receptor | ||||||||||||||||||
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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 / hormone activity / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / transmembrane signaling receptor activity / 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 / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / positive regulation of peptidyl-serine phosphorylation / G alpha (12/13) signalling events / extracellular vesicle / glucose homeostasis / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / 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 / Ras protein signal transduction / G alpha (q) signalling events / secretory granule lumen / Extra-nuclear estrogen signaling / cell population proliferation / 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 | single particle reconstruction / cryo EM / Resolution: 2.1 Å | ||||||||||||||||||
![]() | Belousoff MJ / 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 MJ / Zhao P / Ang SY / Truong TT / Kooistra AJ / Underwood CR / Egebjerg T / Stewart GD / Liang YL / Glukhova A / Venugopal H / Christopoulos A / Furness SGB / Miller LJ ...Authors: Zhang X / Belousoff MJ / Zhao P / Ang SY / Truong TT / Kooistra AJ / Underwood CR / Egebjerg T / Stewart GD / Liang YL / Glukhova A / Venugopal H / Christopoulos A / Furness SGB / Miller LJ / Runge SR / Gloriam DE / Langmead CJ / Danev R / Sexton PM / Wootten D | ||||||||||||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 272.4 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 32.2 KB 32.2 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11.3 KB | Display | ![]() |
Images | ![]() | 41.9 KB | ||
Masks | ![]() | 125 MB | ![]() | |
Others | ![]() ![]() ![]() ![]() ![]() | 31.5 MB 32.1 MB 98.3 MB 98.6 MB 98.6 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6x18MC ![]() 6x19C ![]() 6x1aC C: citing same article ( M: atomic model generated by this map |
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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
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.5 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
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Projections & Slices |
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Density Histograms |
-Additional map: #1
File | emd_21992_additional_1.map | ||||||||||||
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Density Histograms |
-Additional map: Focussed refinement on extra-cellular domain
File | emd_21992_additional_2.map | ||||||||||||
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Annotation | Focussed refinement on extra-cellular domain | ||||||||||||
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Density Histograms |
-Additional map: unsharpened post-processed map
File | emd_21992_additional_3.map | ||||||||||||
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Annotation | unsharpened post-processed map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_21992_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_21992_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
+Entire : GLP-1 peptide hormone bound to Glucagon-Like peptide-1 (GLP-1) Re...
+Supramolecule #1: GLP-1 peptide hormone bound to Glucagon-Like peptide-1 (GLP-1) Re...
+Supramolecule #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms sh...
+Supramolecule #3: Nanobody 35
+Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: Nanobody35
+Macromolecule #5: Glucagon
+Macromolecule #6: Glucagon-like peptide 1 receptor
+Macromolecule #7: water
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 3.5 mg/mL |
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Buffer | pH: 7.4 |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |