7RTB

Peptide-19 bound to the Glucagon-Like Peptide-1 Receptor (GLP-1R)


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.14 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.0 of the entry. See complete history


Literature

Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor.

Johnson, R.M.Zhang, X.Piper, S.J.Nettleton, T.J.Vandekolk, T.H.Langmead, C.J.Danev, R.Sexton, P.M.Wootten, D.

(2021) Biochem Biophys Res Commun 578: 84-90

  • DOI: 10.1016/j.bbrc.2021.09.016
  • Primary Citation of Related Structures:  
    7RTB

  • PubMed Abstract: 
  • Dual agonists that can activate both the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIPR) have demonstrated high efficacy for the treatment of metabolic disease. Peptide-19 is a prototypical dual agonist that has high potency at both GLP-1R and GIPR but has a distinct signalling profile relative to the native peptides at the cognate receptors ...

    Dual agonists that can activate both the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIPR) have demonstrated high efficacy for the treatment of metabolic disease. Peptide-19 is a prototypical dual agonist that has high potency at both GLP-1R and GIPR but has a distinct signalling profile relative to the native peptides at the cognate receptors. In this study, we solved the structure of peptide-19 bound to the GLP-1R in complex with Gs protein, and compared the structure and dynamics of this complex to that of published structures of GLP-1R:Gs in complex with other receptor agonists. Unlike other peptide-bound receptor complexes, peptide-19:GLP-1R:Gs demonstrated a more open binding pocket where transmembrane domain (TM) 6, TM7 and the interconnecting extracellular loop 3 (ECL3) were located away from the peptide, with no interactions between peptide-19 and TM6/ECL3. Analysis of conformational variance of the complex revealed that peptide-19 was highly dynamic and underwent binding and unbinding motions facilitated by the more open TM binding pocket. Both the consensus structure of the GLP-1R complex with peptide-19 and the dynamics of this complex were distinct from previously described GLP-1R structures providing unique insights into the mode of GLP-1R activation by this dual agonist.


    Organizational Affiliation

    Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia. Electronic address: denise.wootten@monash.edu.



Macromolecules
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Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(s) subunit alpha isoforms shortA394Homo sapiensMutation(s): 0 
Gene Names: GNASGNAS1GSP
Membrane Entity: Yes 
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Find proteins for P63092 (Homo sapiens)
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PHAROS:  P63092
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UniProt GroupP63092
Protein Feature View
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Entity ID: 2
MoleculeChainsSequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1B339Homo sapiensMutation(s): 0 
Gene Names: GNB1
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Find proteins for P62873 (Homo sapiens)
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PHAROS:  P62873
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Entity ID: 3
MoleculeChainsSequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2C [auth G]58Homo sapiensMutation(s): 0 
Gene Names: GNG2
Membrane Entity: Yes 
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Entity ID: 4
MoleculeChainsSequence LengthOrganismDetailsImage
Nb35D [auth N]128Lama glamaMutation(s): 0 
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Entity ID: 5
MoleculeChainsSequence LengthOrganismDetailsImage
Glucagon-like peptide 1 receptorE [auth R]490Homo sapiensMutation(s): 1 
Gene Names: GLP1R
Membrane Entity: Yes 
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Find proteins for P43220 (Homo sapiens)
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Entity ID: 6
MoleculeChainsSequence LengthOrganismDetailsImage
Peptide-19F [auth P]38synthetic constructMutation(s): 0 
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Small Molecules
Modified Residues  1 Unique
IDChainsTypeFormula2D DiagramParent
AIB
Query on AIB
F [auth P]L-PEPTIDE LINKINGC4 H9 N O2ALA
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.14 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Health and Medical Research Council (NHMRC, Australia)Japan1150083
National Health and Medical Research Council (NHMRC, Australia)Japan1126857
National Health and Medical Research Council (NHMRC, Australia)Japan1184726
National Health and Medical Research Council (NHMRC, Australia)Japan1154434
National Health and Medical Research Council (NHMRC, Australia)Japan1155302
Australian Research Council (ARC)JapanIC200100052
Japan Science and TechnologyJapan18069571

Revision History  (Full details and data files)

  • Version 1.0: 2021-10-06
    Type: Initial release