6DKJ

human GIPR ECD and Fab complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


This is version 1.0 of the entry. See complete history


Literature

Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models.

Killion, E.A.Wang, J.Yie, J.Shi, S.D.Bates, D.Min, X.Komorowski, R.Hager, T.Deng, L.Atangan, L.Lu, S.C.Kurzeja, R.J.M.Sivits, G.Lin, J.Chen, Q.Wang, Z.Thibault, S.A.Abbott, C.M.Meng, T.Clavette, B.Murawsky, C.M.Foltz, I.N.Rottman, J.B.Hale, C.Veniant, M.M.Lloyd, D.J.

(2018) Sci Transl Med 10

  • DOI: https://doi.org/10.1126/scitranslmed.aat3392
  • Primary Citation of Related Structures:  
    6DKJ

  • PubMed Abstract: 

    Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.


  • Organizational Affiliation

    Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fab heavy chainA [auth H],
D [auth A]
223Homo sapiensMutation(s): 0 
UniProt
Find proteins for P0DOX5 (Homo sapiens)
Explore P0DOX5 
Go to UniProtKB:  P0DOX5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0DOX5
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Fab light chainB [auth L],
E [auth B]
214Homo sapiensMutation(s): 0 
UniProt
Find proteins for V9HW34 (Homo sapiens)
Explore V9HW34 
Go to UniProtKB:  V9HW34
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupV9HW34
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Gastric inhibitory polypeptide receptorC,
F [auth D]
117Homo sapiensMutation(s): 0 
Gene Names: GIPR
UniProt & NIH Common Fund Data Resources
Find proteins for P48546 (Homo sapiens)
Explore P48546 
Go to UniProtKB:  P48546
PHAROS:  P48546
GTEx:  ENSG00000010310 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48546
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.907α = 90
b = 63.649β = 92.56
c = 159.099γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-05-08
    Type: Initial release