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- EMDB-24794: GLP-1 receptor bound with Pfizer small molecule agonist -

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Basic information

Entry
Database: EMDB / ID: EMD-24794
TitleGLP-1 receptor bound with Pfizer small molecule agonist
Map dataEM density map for GLP1R
Sample
  • Complex: agonist bound GLP1 receptor
    • Protein or peptide: Glucagon-like peptide 1 receptor
  • Ligand: 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
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 / response to psychosocial stress / regulation of heart contraction / peptide hormone binding / activation of adenylate cyclase activity / negative regulation of blood pressure ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / response to psychosocial stress / regulation of heart contraction / peptide hormone binding / activation of adenylate cyclase activity / negative regulation of blood pressure / cAMP-mediated signaling / 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
Glucagon-like peptide 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsLiu Y / Dias JM / Han S
Funding support1 items
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, 2021-
Header (metadata) releaseJun 8, 2022-
Map releaseJun 8, 2022-
UpdateJul 6, 2022-
Current statusJul 6, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_24794.png

Downloads & links

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Map

FileDownload / File: emd_24794.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEM density map for GLP1R
Voxel sizeX=Y=Z: 0.848 Å
Density
Contour LevelBy AUTHOR: 4.2
Minimum - Maximum-11.989312 - 12.992233
Average (Standard dev.)0.059848763 (±0.6375074)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 135.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : agonist bound GLP1 receptor

EntireName: agonist bound GLP1 receptor
Components
  • Complex: agonist bound GLP1 receptor
    • Protein or peptide: Glucagon-like peptide 1 receptor
  • Ligand: 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

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Supramolecule #1: agonist bound GLP1 receptor

SupramoleculeName: agonist bound GLP1 receptor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: GLP1 receptor is stabilized by StaR mutations
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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Macromolecule #1: Glucagon-like peptide 1 receptor

MacromoleculeName: Glucagon-like peptide 1 receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.701004 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: RPQGATVSLW ETVQKWREYR RQCQRSLTED PPPATDLFCN RTFDEYACWP DGEPGSFVNV SCPWYLPWAS SVPQGHVYRF CTAEGLWLQ KDNSSLPWRD LSECEESKRG ERSSPEEQLL FLYYIYTVGY ALSFSALVIA SAILLGFRHL HCTRNYIHLN L FASFILRA ...String:
RPQGATVSLW ETVQKWREYR RQCQRSLTED PPPATDLFCN RTFDEYACWP DGEPGSFVNV SCPWYLPWAS SVPQGHVYRF CTAEGLWLQ KDNSSLPWRD LSECEESKRG ERSSPEEQLL FLYYIYTVGY ALSFSALVIA SAILLGFRHL HCTRNYIHLN L FASFILRA LSVFIKDAAL KWMYSTRAQQ HEWDGLLRYQ DSLSCRLVFL LMQYCVAANY YWLLVEGVYL YTLLAFSVAS EQ WIFRLYV SIGWGVPLLF VVPWGIVKYL AEDEGCWTRN SNMNYWLIIR LPILFAIGVN FLIFVRVICI VVSKLKANEM CKT DIQCRL AKSTLTLIPL LGTHEVIFAF VMDEHARGTL RFIKLFTELS FTSFQGLMVA ILYCFVNNEV QLEFRKSWER WRL

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Macromolecule #2: 2-[(4-{6-[(2,4-difluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl...

MacromoleculeName: 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
type: ligand / ID: 2 / Number of copies: 1 / Formula: 82L
Molecular weightTheoretical: 586.632 Da
Chemical component information

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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.075 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: GRAPHENE OXIDE / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK II / Details: -2 blotting force 4S blotting time.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Sampling interval: 5.0 µm / Digitization - Frames/image: 1-20 / Number real images: 19000 / Average electron dose: 2.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus min: 1.0 µm / Nominal magnification: 29000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

DetailsMovies were aligned with MotionCorr2, particle selected with Gautomatch, processed with Relion2 and CisTEM
Particle selectionNumber selected: 6000000
CTF correctionSoftware - Name: Gctf
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5uz7

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 120000
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationNumber classes: 8 / Software - Name: RELION
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6b3j

RefinementProtocol: RIGID BODY FIT
Output model

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

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