1II4

CRYSTAL STRUCTURE OF SER252TRP APERT MUTANT FGF RECEPTOR 2 (FGFR2) IN COMPLEX WITH FGF2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.238 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome.

Ibrahimi, O.A.Eliseenkova, A.V.Plotnikov, A.N.Yu, K.Ornitz, D.M.Mohammadi, M.

(2001) Proc Natl Acad Sci U S A 98: 7182-7187

  • DOI: https://doi.org/10.1073/pnas.121183798
  • Primary Citation of Related Structures:  
    1II4, 1IIL

  • PubMed Abstract: 

    Apert syndrome (AS) is characterized by craniosynostosis (premature fusion of cranial sutures) and severe syndactyly of the hands and feet. Two activating mutations, Ser-252 --> Trp and Pro-253 --> Arg, in fibroblast growth factor receptor 2 (FGFR2) account for nearly all known cases of AS. To elucidate the mechanism by which these substitutions cause AS, we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2). These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. Moreover, based on these structures and sequence alignment of the FGF family, we propose that the Pro-253 --> Arg mutation will indiscriminately increase the affinity of FGFR2 toward any FGF. In contrast, the Ser-252 --> Trp mutation will selectively enhance the affinity of FGFR2 toward a limited subset of FGFs. These predictions are consistent with previous biochemical data describing the effects of AS mutations on FGF binding. Alterations in FGFR2 ligand affinity and specificity may allow inappropriate autocrine or paracrine activation of FGFR2. Furthermore, the distinct gain-of-function interactions observed in each crystal structure provide a model to explain the phenotypic variability among AS patients.


  • Organizational Affiliation

    Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HEPARIN-BINDING GROWTH FACTOR 2
A, B, C, D
155Homo sapiensMutation(s): 2 
UniProt & NIH Common Fund Data Resources
Find proteins for P09038 (Homo sapiens)
Explore P09038 
Go to UniProtKB:  P09038
PHAROS:  P09038
GTEx:  ENSG00000138685 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09038
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
FIBROBLAST GROWTH FACTOR RECEPTOR 2
E, F, G, H
220Homo sapiensMutation(s): 1 
EC: 2.7.1.112
UniProt & NIH Common Fund Data Resources
Find proteins for P21802 (Homo sapiens)
Explore P21802 
Go to UniProtKB:  P21802
PHAROS:  P21802
GTEx:  ENSG00000066468 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21802
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.238 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.97α = 89.98
b = 72.657β = 89.7
c = 89.739γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-05-09
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references
  • Version 1.4: 2023-08-16
    Changes: Data collection, Refinement description