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- PDB-7lcj: PF 06882961 bound to the glucagon-like peptide-1 receptor (GLP-1R... -

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Basic information

Entry
Database: PDB / ID: 7lcj
TitlePF 06882961 bound to the glucagon-like peptide-1 receptor (GLP-1R):Gs complex
ComponentsGlucagon-like peptide 1 receptor
KeywordsMEMBRANE PROTEIN / GPCR / small molecule agonist
Function / homology
Function and homology information


glucagon-like peptide 1 receptor activity / glucagon receptor activity / positive regulation of blood pressure / hormone secretion / 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 / positive regulation of blood pressure / hormone secretion / 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 / 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. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily ...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. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / 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-UK4 / Glucagon-like peptide 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.82 Å
AuthorsBelousoff, M.J. / Johnson, R.M. / Drulyte, I. / Yu, L. / Kotecha, A. / Danev, R. / Wootten, D. / Zhang, X. / Sexton, P.M.
Funding support Australia, Japan, 5items
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, 2021Deposition site: RCSB / Processing site: RCSB
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Revision 1.1May 19, 2021Group: Database references / Category: citation
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Revision 1.3Nov 20, 2024Group: Data collection / Structure summary
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Assembly

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


Theoretical massNumber of molelcules
Total (without water)57,3042
Polymers56,7481
Non-polymers5561
Water30617
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


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
#2: Chemical 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


Mass: 555.599 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H30FN5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: Receptor only portion of GLP1:Gs complex with a small molecule agonist bound: PF-06882961
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 459000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0093351
ELECTRON MICROSCOPYf_angle_d0.8724571
ELECTRON MICROSCOPYf_dihedral_angle_d21.947443
ELECTRON MICROSCOPYf_chiral_restr0.053497
ELECTRON MICROSCOPYf_plane_restr0.005557

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