5NX2

Crystal structure of thermostabilised full-length GLP-1R in complex with a truncated peptide agonist at 3.7 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.70 Å
  • R-Value Free: 0.334 
  • R-Value Work: 0.285 
  • R-Value Observed: 0.287 

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This is version 3.1 of the entry. See complete history


Literature

Crystal structure of the GLP-1 receptor bound to a peptide agonist.

Jazayeri, A.Rappas, M.Brown, A.J.H.Kean, J.Errey, J.C.Robertson, N.J.Fiez-Vandal, C.Andrews, S.P.Congreve, M.Bortolato, A.Mason, J.S.Baig, A.H.Teobald, I.Dore, A.S.Weir, M.Cooke, R.M.Marshall, F.H.

(2017) Nature 546: 254-258

  • DOI: https://doi.org/10.1038/nature22800
  • Primary Citation of Related Structures:  
    5NX2

  • PubMed Abstract: 

    Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.


  • Organizational Affiliation

    Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glucagon-like peptide 1 receptor422Homo sapiensMutation(s): 12 
Gene Names: GLP1R
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P43220 (Homo sapiens)
Explore P43220 
Go to UniProtKB:  P43220
PHAROS:  P43220
GTEx:  ENSG00000112164 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP43220
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
truncated peptide agonist10synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
C
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.70 Å
  • R-Value Free: 0.334 
  • R-Value Work: 0.285 
  • R-Value Observed: 0.287 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.435α = 90
b = 94.435β = 90
c = 163.905γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2017-06-14
    Type: Initial release
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 3.0: 2023-11-15
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 3.1: 2024-01-17
    Changes: Refinement description