+Open data
-Basic information
Entry | Database: PDB / ID: 7s15 | ||||||
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Title | GLP-1 receptor bound with Pfizer small molecule agonist | ||||||
Components | Glucagon-like peptide 1 receptor | ||||||
Keywords | MEMBRANE PROTEIN / GLP-1R / GPCR | ||||||
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 / Glucagon-type ligand receptors / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / transmembrane signaling receptor activity / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / learning or memory / cell surface receptor signaling pathway / membrane / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å | ||||||
Authors | Liu, Y. / Dias, J.M. / Han, S. | ||||||
Funding support | 1items
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Citation | Journal: J Med Chem / Year: 2022 Title: A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor. Authors: David A Griffith / David J Edmonds / Jean-Philippe Fortin / Amit S Kalgutkar / J Brent Kuzmiski / Paula M Loria / Aditi R Saxena / Scott W Bagley / Clare Buckeridge / John M Curto / David R ...Authors: David A Griffith / David J Edmonds / Jean-Philippe Fortin / Amit S Kalgutkar / J Brent Kuzmiski / Paula M Loria / Aditi R Saxena / Scott W Bagley / Clare Buckeridge / John M Curto / David R Derksen / João M Dias / Matthew C Griffor / Seungil Han / V Margaret Jackson / Margaret S Landis / Daniel Lettiere / Chris Limberakis / Yuhang Liu / Alan M Mathiowetz / Jayesh C Patel / David W Piotrowski / David A Price / Roger B Ruggeri / David A Tess / Abstract: Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the ...Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7s15.cif.gz | 80 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7s15.ent.gz | 61.7 KB | Display | PDB format |
PDBx/mmJSON format | 7s15.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7s15_validation.pdf.gz | 840.4 KB | Display | wwPDB validaton report |
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Full document | 7s15_full_validation.pdf.gz | 846.4 KB | Display | |
Data in XML | 7s15_validation.xml.gz | 23.1 KB | Display | |
Data in CIF | 7s15_validation.cif.gz | 33.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/s1/7s15 ftp://data.pdbj.org/pub/pdb/validation_reports/s1/7s15 | HTTPS FTP |
-Related structure data
Related structure data | 24794MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 46701.004 Da / Num. of mol.: 1 Mutation: I146Y, A208R, Q213E, S219R, L260A, Y291A, L339E, K346Q Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GLP1R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P43220 |
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#2: Chemical | ChemComp-82L / |
Has ligand of interest | Y |
-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 | Name: agonist bound GLP1 receptor / Type: COMPLEX / Details: GLP1 receptor is stabilized by StaR mutations / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 0.075 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K / Details: -2 blotting force 4S blotting time |
-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 / Nominal magnification: 29000 X / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 2 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 19000 |
Image scans | Sampling size: 5 µm / Movie frames/image: 20 / Used frames/image: 1-20 |
-Processing
Software | Name: PHENIX / Version: 1.16_3549: / Classification: refinement | ||||||||||||||||||||||||||||||
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EM software |
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Image processing | Details: Movies were aligned with MotionCorr2, particle selected with Gautomatch, processed with Relion2 and CisTEM | ||||||||||||||||||||||||||||||
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 6000000 | ||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 120000 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT | ||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6B3J | ||||||||||||||||||||||||||||||
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