2JKQ

Focal Adhesion Kinase catalytic domain in complex with bis-anilino pyrimidine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.217 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Crystal Structures of the Fak Kinase in Complex with Tae226 and Related Bis-Anilino Pyrimidine Inhibitors Reveal a Helical Dfg Conformation.

Lietha, D.Eck, M.J.

(2008) PLoS One 3: E3800

  • DOI: https://doi.org/10.1371/journal.pone.0003800
  • Primary Citation of Related Structures:  
    2JKK, 2JKM, 2JKO, 2JKQ

  • PubMed Abstract: 

    Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase required for cell migration, proliferation and survival. FAK overexpression has been documented in diverse human cancers and is associated with a poor clinical outcome. Recently, a novel bis-anilino pyrimidine inhibitor, TAE226, was reported to efficiently inhibit FAK signaling, arrest tumor growth and invasion and prolong the life of mice with glioma or ovarian tumor implants. Here we describe the crystal structures of the FAK kinase bound to TAE226 and three related bis-anilino pyrimidine compounds. TAE226 induces a conformation of the N-terminal portion of the kinase activation loop that is only observed in FAK, but is distinct from the conformation in both the active and inactive states of the kinase. This conformation appears to require a glycine immediately N-terminal to the "DFG motif", which adopts a helical conformation stabilized by interactions with TAE226. The presence of a glycine residue in this position contributes to the specificity of TAE226 and related compounds for FAK. Our work highlights the fact that kinases can access conformational space that is not necessarily utilized for their native catalytic regulation, and that such conformations can explain and be exploited for inhibitor specificity.


  • Organizational Affiliation

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FOCAL ADHESION KINASE 1276Gallus gallusMutation(s): 0 
EC: 2.7.10.2
UniProt
Find proteins for Q00944 (Gallus gallus)
Explore Q00944 
Go to UniProtKB:  Q00944
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00944
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
VG8
Query on VG8

Download Ideal Coordinates CCD File 
B [auth A]4-(1,4'-bipiperidin-1'-yl)-7-({5-chloro-2-[(2-methoxyphenyl)amino]pyrimidin-4-yl}amino)-2-methyl-2,3-dihydro-1H-isoindol-1-one
C30 H36 Cl N7 O2
CXZCUCWQLXRDJA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
VG8 PDBBind:  2JKQ IC50: 7.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.217 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.523α = 90
b = 44.887β = 95.42
c = 66.435γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-09-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2019-04-03
    Changes: Data collection, Other, Source and taxonomy
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description