5YQZ

Structure of the glucagon receptor in complex with a glucagon analogue


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.232 
  • R-Value Observed: 0.233 

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This is version 2.1 of the entry. See complete history


Literature

Structure of the glucagon receptor in complex with a glucagon analogue.

Zhang, H.Qiao, A.Yang, L.Van Eps, N.Frederiksen, K.S.Yang, D.Dai, A.Cai, X.Zhang, H.Yi, C.Cao, C.He, L.Yang, H.Lau, J.Ernst, O.P.Hanson, M.A.Stevens, R.C.Wang, M.W.Reedtz-Runge, S.Jiang, H.Zhao, Q.Wu, B.

(2018) Nature 553: 106-110

  • DOI: https://doi.org/10.1038/nature25153
  • Primary Citation of Related Structures:  
    5YQZ

  • PubMed Abstract: 

    Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases. Previous work has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved. These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 Å-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR-NNC0640-mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation-which requires conformational changes of the stalk, first extracellular loop and TMD-that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs.


  • Organizational Affiliation

    CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glucagon receptor,Endolysin,Glucagon receptorA [auth R]575Homo sapiensTequatrovirus T4Mutation(s): 3 
Gene Names: GCGReT4Tp126
EC: 3.2.1.17
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P47871 (Homo sapiens)
Explore P47871 
Go to UniProtKB:  P47871
PHAROS:  P47871
GTEx:  ENSG00000215644 
Find proteins for P00720 (Enterobacteria phage T4)
Explore P00720 
Go to UniProtKB:  P00720
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP00720P47871
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Glucagon analogueB [auth P]28Homo sapiensMutation(s): 0 
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P01275 (Homo sapiens)
Explore P01275 
Go to UniProtKB:  P01275
PHAROS:  P01275
GTEx:  ENSG00000115263 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01275
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranoseC [auth A],
D [auth B]
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.232 
  • R-Value Observed: 0.233 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.12α = 90
b = 108.79β = 90
c = 216.25γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata scaling
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Science Foundation (China)China31422017
National Science Foundation (China)China81525024

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-17
    Type: Initial release
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-11-22
    Changes: Data collection, Database references, Refinement description, Structure summary