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- PDB-7s15: GLP-1 receptor bound with Pfizer small molecule agonist -

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Basic information

Entry
Database: PDB / ID: 7s15
TitleGLP-1 receptor bound with Pfizer small molecule agonist
ComponentsGlucagon-like peptide 1 receptorGlucagon-like peptide-1 receptor
KeywordsMEMBRANE 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 / response to psychosocial stress / peptide hormone binding / cAMP-mediated signaling / activation of adenylate cyclase activity ...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 / response to psychosocial stress / peptide hormone binding / cAMP-mediated signaling / activation of adenylate cyclase activity / 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
: / GPCR, family 2, glucagon-like peptide-1 receptor / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. ...: / GPCR, family 2, glucagon-like peptide-1 receptor / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2.
Similarity search - Domain/homology
Chem-82L / Glucagon-like peptide 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsLiu, Y. / Dias, J.M. / Han, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: 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
DepositionSep 1, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 8, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 15, 2022Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 6, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: Glucagon-like peptide 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2882
Polymers46,7011
Non-polymers5871
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area23210 Å2
MethodPISA

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Components

#1: Protein Glucagon-like peptide 1 receptor / Glucagon-like peptide-1 receptor / GLP-1 receptor / GLP-1-R / GLP-1R


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
#2: Chemical ChemComp-82L / 2-[(4-{6-[(2,4-difluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid


Mass: 586.632 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H32F2N6O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: agonist bound GLP1 receptor / Type: COMPLEX / Details: GLP1 receptor is stabilized by StaR mutations / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 0.075 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K / Details: -2 blotting force 4S blotting time

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 29000 X / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 2 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 19000
Image scansSampling size: 5 µm / Movie frames/image: 20 / Used frames/image: 1-20

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameCategory
1Gautomatchparticle selection
2SerialEMimage acquisition
4GctfCTF correction
7Cootmodel fitting
9RELIONinitial Euler assignment
10RELIONfinal Euler assignment
11RELIONclassification
12RELION3D reconstruction
13PHENIXmodel refinement
Image processingDetails: Movies were aligned with MotionCorr2, particle selected with Gautomatch, processed with Relion2 and CisTEM
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6000000
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 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 buildingProtocol: RIGID BODY FIT
Atomic model buildingPDB-ID: 6B3J

6b3j

Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0063309
ELECTRON MICROSCOPYf_angle_d0.7724511
ELECTRON MICROSCOPYf_dihedral_angle_d10.681915
ELECTRON MICROSCOPYf_chiral_restr0.045485
ELECTRON MICROSCOPYf_plane_restr0.004588

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