4F63

Crystal structure of Human Fibroblast Growth Factor Receptor 1 Kinase domain in complex with compound 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.232 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Protein-Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase.

Norman, R.A.Schott, A.K.Andrews, D.M.Breed, J.Foote, K.M.Garner, A.P.Ogg, D.Orme, J.P.Pink, J.H.Roberts, K.Rudge, D.A.Thomas, A.P.Leach, A.G.

(2012) J Med Chem 55: 5003-5012

  • DOI: https://doi.org/10.1021/jm3004043
  • Primary Citation of Related Structures:  
    4F63, 4F64, 4F65

  • PubMed Abstract: 

    The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.


  • Organizational Affiliation

    AstraZeneca Pharmaceuticals , Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fibroblast growth factor receptor 1
A, B
309Homo sapiensMutation(s): 2 
Gene Names: FGFR1BFGFRCEKFGFBRFLGFLT2HBGFR
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11362 (Homo sapiens)
Explore P11362 
Go to UniProtKB:  P11362
PHAROS:  P11362
GTEx:  ENSG00000077782 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11362
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
0S7 BindingDB:  4F63 IC50: min: 501.19, max: 2511.89 (nM) from 2 assay(s)
PDBBind:  4F63 IC50: 500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.232 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 208.306α = 90
b = 57.477β = 107.42
c = 65.452γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
AMoREphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata 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: 2012-06-06
    Type: Initial release
  • Version 1.1: 2012-06-27
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description