4J99

Crystal Structure of FGF Receptor 2 (FGFR2) Kinase Domain Harboring the Gain-of-Function K659T Mutation.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.206 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Cracking the Molecular Origin of Intrinsic Tyrosine Kinase Activity through Analysis of Pathogenic Gain-of-Function Mutations.

Chen, H.Huang, Z.Dutta, K.Blais, S.Neubert, T.A.Li, X.Cowburn, D.Traaseth, N.J.Mohammadi, M.

(2013) Cell Rep 4: 376-384

  • DOI: https://doi.org/10.1016/j.celrep.2013.06.025
  • Primary Citation of Related Structures:  
    4J95, 4J96, 4J97, 4J98, 4J99

  • PubMed Abstract: 

    The basal (ligand-independent) kinase activity of receptor tyrosine kinases (RTKs) promotes trans-phosphorylation on activation loop tyrosines upon ligand-induced receptor dimerization, thus upregulating intrinsic kinase activity and triggering intracellular signaling. To understand the molecular determinants of intrinsic kinase activity, we used X-ray crystallography and NMR spectroscopy to analyze pathogenic FGF receptor mutants with gradations in gain-of-function activity. These structural analyses revealed a "two-state" dynamic equilibrium model whereby the kinase toggles between an "inhibited," structurally rigid ground state and a more dynamic and heterogeneous active state. The pathogenic mutations have different abilities to shift this equilibrium toward the active state. The increase in the fractional population of FGF receptors in the active state correlates with the degree of gain-of-function activity and clinical severity. Our data demonstrate that the fractional population of RTKs in the active state determines intrinsic kinase activity and underscore how a slight increase in the active population of kinases can have grave consequences for human health.


  • Organizational Affiliation

    Department of Biochemistry and Molecular 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
Fibroblast growth factor receptor 2
A, B, C, D
324Homo sapiensMutation(s): 2 
Gene Names: BEKFGFR2KGFRKSAM
EC: 2.7.10.1
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
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ACP
Query on ACP

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C],
P [auth D]
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER
C11 H18 N5 O12 P3
UFZTZBNSLXELAL-IOSLPCCCSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A]
G [auth A]
H [auth B]
J [auth B]
K [auth C]
E [auth A],
G [auth A],
H [auth B],
J [auth B],
K [auth C],
N [auth C],
O [auth D]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
MG
Query on MG

Download Ideal Coordinates CCD File 
M [auth C],
Q [auth D],
R [auth D]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.206 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 278.508α = 90
b = 78.395β = 101.02
c = 73.197γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
AMoREphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-08-07
    Type: Initial release
  • Version 1.1: 2013-08-21
    Changes: Database references
  • Version 1.2: 2016-12-28
    Changes: Structure summary
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description