6GCW

Focal Adhesion Kinase catalytic domain in complex with irreversible inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.220 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase.

Yen-Pon, E.Li, B.Acebron-Garcia-de-Eulate, M.Tomkiewicz-Raulet, C.Dawson, J.Lietha, D.Frame, M.C.Coumoul, X.Garbay, C.Etheve-Quelquejeu, M.Chen, H.

(2018) ACS Chem Biol 13: 2067-2073

  • DOI: https://doi.org/10.1021/acschembio.8b00250
  • Primary Citation of Related Structures:  
    6GCR, 6GCW, 6GCX

  • PubMed Abstract: 

    Focal Adhesion Kinase signaling pathway and its functions have been involved in the development and aggressiveness of tumor malignancy, it then presents a promising cancer therapeutic target. Several reversible FAK inhibitors have been developed and are being conducted in clinical trials. On the other hand, irreversible covalent inhibitors would bring many desirable pharmacological features including high potency and increased duration of action. Herein we report the structure-guided development of the first highly potent and irreversible inhibitor of the FAK kinase. This inhibitor showed a very potent decrease of autophosphorylation of FAK in squamous cell carcinoma. A cocrystal structure of the FAK kinase domain in complex with this compound revealed the inhibitor binding mode within the ATP binding site and confirmed the covalent linkage between the targeted Cys427 of the protein and the inhibitor.


  • Organizational Affiliation

    Chemistry of RNA, Nucleosides, Peptides and Heterocycles, CNRS UMR8601 , Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale , 45 rue des Saints-Pères , 75270 Paris Cedex 06 , France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Focal adhesion kinase 1
A, B
276Gallus gallusMutation(s): 0 
Gene Names: PTK2FAKFAK1
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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EUQ
Query on EUQ

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
2-[[5-chloranyl-2-[[4-[[[1-[2-(propanoylamino)ethyl]-1,2,3-triazol-4-yl]methylamino]methyl]phenyl]amino]pyrimidin-4-yl]amino]-~{N}-methyl-benzamide
C27 H31 Cl N10 O2
NQZYJQAUOJXIDJ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
EUQ Binding MOAD:  6GCW IC50: 4.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.220 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.916α = 90
b = 119.798β = 90.56
c = 52.81γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2019-05-01
    Type: Initial release
  • Version 1.1: 2019-10-02
    Changes: Data collection, Database references