3RHX

Crystal structure of the catalytic domain of FGFR1 kinase in complex with ARQ 069


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.205 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited kinases: discovery of ATP-independent inhibitors of fibroblast growth factor receptor.

Eathiraj, S.Palma, R.Hirschi, M.Volckova, E.Nakuci, E.Castro, J.Chen, C.R.Chan, T.C.France, D.S.Ashwell, M.A.

(2011) J Biol Chem 286: 20677-20687

  • DOI: https://doi.org/10.1074/jbc.M110.213736
  • Primary Citation of Related Structures:  
    3RHX, 3RI1

  • PubMed Abstract: 

    Protein kinase inhibitors with enhanced selectivity can be designed by optimizing binding interactions with less conserved inactive conformations because such inhibitors will be less likely to compete with ATP for binding and therefore may be less impacted by high intracellular concentrations of ATP. Analysis of the ATP-binding cleft in a number of inactive protein kinases, particularly in the autoinhibited conformation, led to the identification of a previously undisclosed non-polar region in this cleft. This ATP-incompatible hydrophobic region is distinct from the previously characterized hydrophobic allosteric back pocket, as well as the main pocket. Generalized hypothetical models of inactive kinases were constructed and, for the work described here, we selected the fibroblast growth factor receptor (FGFR) tyrosine kinase family as a case study. Initial optimization of a FGFR2 inhibitor identified from a library of commercial compounds was guided using structural information from the model. We describe the inhibitory characteristics of this compound in biophysical, biochemical, and cell-based assays, and have characterized the binding mode using x-ray crystallographic studies. The results demonstrate, as expected, that these inhibitors prevent activation of the autoinhibited conformation, retain full inhibitory potency in the presence of physiological concentrations of ATP, and have favorable inhibitory activity in cancer cells. Given the widespread regulation of kinases by autoinhibitory mechanisms, the approach described herein provides a new paradigm for the discovery of inhibitors by targeting inactive conformations of protein kinases.


  • Organizational Affiliation

    ArQule, Inc, Woburn, Massachusetts 01801, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Basic fibroblast growth factor receptor 1A [auth B],
B [auth A]
306Homo sapiensMutation(s): 2 
Gene Names: FGFR1FGFBRFLGFLT2
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
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3RH
Query on 3RH

Download Ideal Coordinates CCD File 
C [auth B],
F [auth A]
(6S)-6-phenyl-5,6-dihydrobenzo[h]quinazolin-2-amine
C18 H15 N3
BMOQBIIJPJVMDI-INIZCTEOSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth B]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth B],
G [auth A],
H [auth A],
I [auth A],
J [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3RH BindingDB:  3RHX IC50: min: 840, max: 1230 (nM) from 2 assay(s)
Binding MOAD:  3RHX IC50: 840 (nM) from 1 assay(s)
PDBBind:  3RHX IC50: 840 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.205 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 208.43α = 90
b = 57.865β = 107.22
c = 65.686γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
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: 2011-05-04
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-10-19
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations