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Yorodumi- PDB-6x1a: Non peptide agonist PF-06882961, bound to Glucagon-Like peptide-1... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6x1a | ||||||||||||||||||
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Title | Non peptide agonist PF-06882961, bound to Glucagon-Like peptide-1 (GLP-1) Receptor | ||||||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / G-coupled protein receptor / GPCR / non-peptide agonist | ||||||||||||||||||
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 / activation of adenylate cyclase activity / response to psychosocial stress / 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 / activation of adenylate cyclase activity / response to psychosocial stress / peptide hormone binding / cAMP-mediated signaling / negative regulation of blood pressure / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / 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) / GTPase binding / 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 / 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 / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||||||||||||||
Biological species | Homo sapiens (human) Lama glama (llama) | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å | ||||||||||||||||||
Authors | Belousoff, M.J. / Zhang, X. / Danev, R. | ||||||||||||||||||
Funding support | Australia, 5items
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Citation | Journal: Mol Cell / Year: 2020 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: Journal: Biorxiv / Year: 2020 Title: Differential GLP-1R binding and activation by peptide and non-peptide agonists Authors: Zhang, X. / Belousoff, M.J. / Zhao, P. / Ang, S.Y. / Truong, T.T. / Kooistra, A.J. / Underwood, C.R. / Egebjerg, T. / Stewart, G.D. / Liang, Y.L. / Glukhova, A. / Venugopal, H. / ...Authors: Zhang, X. / Belousoff, M.J. / Zhao, P. / Ang, S.Y. / Truong, T.T. / Kooistra, A.J. / Underwood, C.R. / Egebjerg, T. / Stewart, G.D. / Liang, Y.L. / Glukhova, A. / Venugopal, H. / Christopoulos, A. / Furness, S.G.B. / Miller, L.J. / Runge, S.R. / Gloriam, D.E. / Langmead, C.J. / Danev, R. / Sexton, P.M. / Wootten, D. | ||||||||||||||||||
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 | 6x1a.cif.gz | 244.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6x1a.ent.gz | 196.9 KB | Display | PDB format |
PDBx/mmJSON format | 6x1a.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6x1a_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 6x1a_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 6x1a_validation.xml.gz | 51.9 KB | Display | |
Data in CIF | 6x1a_validation.cif.gz | 77.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/x1/6x1a ftp://data.pdbj.org/pub/pdb/validation_reports/x1/6x1a | HTTPS FTP |
-Related structure data
Related structure data | 21994MC 6x18C 6x19C C: citing same article (ref.) M: map data used to model this data |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#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: 37413.863 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: 6375.332 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 , 2 types, 2 molecules NR
#4: Antibody | Mass: 13885.439 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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#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 |
-Non-polymers , 2 types, 24 molecules
#6: Chemical | ChemComp-UK4 / |
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#7: Water | ChemComp-HOH / |
-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 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
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 FIELD |
Image recording | Electron dose: 58 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: dev_3714: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 683444 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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