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- EMDB-23275: PF 06882961 bound to the glucagon-like peptide-1 receptor (GLP-1R... -

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Basic information

Entry
Database: EMDB / ID: EMD-23275
TitlePF 06882961 bound to the glucagon-like peptide-1 receptor (GLP-1R):Gs complex
Map dataPost-processed consensus map, cryoSPARC non-uniformed refined
Sample
  • Complex: Receptor only portion of GLP1:Gs complex with a small molecule agonist bound: PF-06882961
    • Protein or peptide: Glucagon-like peptide 1 receptorGlucagon-like peptide-1 receptor
  • Ligand: 2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid
  • Ligand: water
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
Glucagon-like peptide 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.82 Å
AuthorsBelousoff MJ / Johnson RM / Drulyte I / Yu L / Kotecha A / Danev R / Wootten D / Zhang X / Sexton PM
Funding support Australia, Japan, 5 items
OrganizationGrant numberCountry
Australian Research Council (ARC)IC200100052 Australia
National Health and Medical Research Council (NHMRC, Australia)1126857 Australia
National Health and Medical Research Council (NHMRC, Australia)1184726 Australia
National Health and Medical Research Council (NHMRC, Australia)1150083 Australia
Japan Science and Technology18069571 Japan
CitationJournal: Structure / Year: 2021
Title: Evolving cryo-EM structural approaches for GPCR drug discovery.
Authors: Xin Zhang / Rachel M Johnson / Ieva Drulyte / Lingbo Yu / Abhay Kotecha / Radostin Danev / Denise Wootten / Patrick M Sexton / Matthew J Belousoff /
Abstract: G protein-coupled receptors (GPCRs) are the largest class of cell surface drug targets. Advances in stabilization of GPCR:transducer complexes, together with improvements in cryoelectron microscopy ...G protein-coupled receptors (GPCRs) are the largest class of cell surface drug targets. Advances in stabilization of GPCR:transducer complexes, together with improvements in cryoelectron microscopy (cryo-EM) have recently been applied to structure-assisted drug design for GPCR agonists. Nonetheless, limitations in the commercial application of these approaches, including the use of nanobody 35 (Nb35) to aid complex stabilization and the high cost of 300 kV imaging, have restricted broad application of cryo-EM in drug discovery. Here, using the PF 06882961-bound GLP-1R as exemplar, we validated the formation of stable complexes with a modified Gs protein in the absence of Nb35. In parallel, we compare 200 versus 300 kV image acquisition using a Falcon 4 or K3 direct electron detector. Moreover, the 200 kV Glacios-Falcon 4 yielded a 3.2 Å map with clear density for bound drug and multiple structurally ordered waters. Our work paves the way for broader commercial application of cryo-EM for GPCR drug discovery.
History
DepositionJan 11, 2021-
Header (metadata) releaseJan 20, 2021-
Map releaseJan 20, 2021-
UpdateSep 15, 2021-
Current statusSep 15, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.447
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.447
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7lcj
  • Surface level: 0.447
  • Imaged by UCSF Chimera
  • Download
  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7lcj
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23275.png

Downloads & links

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Map

FileDownload / File: emd_23275.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPost-processed consensus map, cryoSPARC non-uniformed refined
Voxel sizeX=Y=Z: 0.823 Å
Density
Contour LevelBy AUTHOR: 0.447 / Movie #1: 0.447
Minimum - Maximum-3.6531053 - 4.7790213
Average (Standard dev.)-0.00036658242 (±0.090519145)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 237.024 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8230.8230.823
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z237.024237.024237.024
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-3.6534.779-0.000

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Supplemental data

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Mask #1

Fileemd_23275_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Receptor focussed refinement, resampled on consensus map

Fileemd_23275_additional_1.map
AnnotationReceptor focussed refinement, resampled on consensus map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half-map1

Fileemd_23275_half_map_1.map
Annotationhalf-map1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half-map2

Fileemd_23275_half_map_2.map
Annotationhalf-map2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Receptor only portion of GLP1:Gs complex with a small molecule ag...

EntireName: Receptor only portion of GLP1:Gs complex with a small molecule agonist bound: PF-06882961
Components
  • Complex: Receptor only portion of GLP1:Gs complex with a small molecule agonist bound: PF-06882961
    • Protein or peptide: Glucagon-like peptide 1 receptorGlucagon-like peptide-1 receptor
  • Ligand: 2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid
  • Ligand: water

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Supramolecule #1: Receptor only portion of GLP1:Gs complex with a small molecule ag...

SupramoleculeName: Receptor only portion of GLP1:Gs complex with a small molecule agonist bound: PF-06882961
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)

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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: 56.748418 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MKTIIALSYI FCLVFADYKD DDDLEVLFQG PARPQGATVS LWETVQKWRE YRRQCQRSLT EDPPPATDLF CNRTFDEYAC WPDGEPGSF VNVSCPWYLP WASSVPQGHV YRFCTAEGLW LQKDNSSLPW RDLSECEESK RGERSSPEEQ LLFLYIIYTV G YALSFSAL ...String:
MKTIIALSYI FCLVFADYKD DDDLEVLFQG PARPQGATVS LWETVQKWRE YRRQCQRSLT EDPPPATDLF CNRTFDEYAC WPDGEPGSF VNVSCPWYLP WASSVPQGHV YRFCTAEGLW LQKDNSSLPW RDLSECEESK RGERSSPEEQ LLFLYIIYTV G YALSFSAL VIASAILLGF RHLHCTRNYI HLNLFASFIL RALSVFIKDA ALKWMYSTAA QQHQWDGLLS YQDSLSCRLV FL LMQYCVA ANYYWLLVEG VYLYTLLAFS VFSEQWIFRL YVSIGWGVPL LFVVPWGIVK YLYEDEGCWT RNSNMNYWLI IRL PILFAI GVNFLIFVRV ICIVVSKLKA NLMCKTDIKC RLAKSTLTLI PLLGTHEVIF AFVMDEHARG TLRFIKLFTE LSFT SFQGL MVAILYCFVN NEVQLEFRKS WERWRLEHLH IQRDSSMKPL KCPTSSLSSG ATAGSSMYTA TCQASCSPAG LEVLF QGPH HHHHHHH

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Macromolecule #2: 2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-...

MacromoleculeName: 2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid
type: ligand / ID: 2 / Number of copies: 1 / Formula: UK4
Molecular weightTheoretical: 555.599 Da
Chemical component information

ChemComp-UK4:
2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 17 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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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

Concentration5 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 459000
FSC plot (resolution estimation)

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