4K8A

Fragment-based discovery of Focal Adhesion Kinase Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.91 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.184 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Fragment-based discovery of focal adhesion kinase inhibitors.

Gradler, U.Bomke, J.Musil, D.Dresing, V.Lehmann, M.Holzemann, G.Greiner, H.Esdar, C.Krier, M.Heinrich, T.

(2013) Bioorg Med Chem Lett 23: 5401-5409

  • DOI: https://doi.org/10.1016/j.bmcl.2013.07.050
  • Primary Citation of Related Structures:  
    4K8A, 4K9Y, 4KAB, 4KAO

  • PubMed Abstract: 

    Chemically diverse fragment hits of focal adhesion kinase (FAK) were discovered by surface plasmon resonance (SPR) screening of our in-house fragment library. Site specific binding of the primary hits was confirmed in a competition setup using a high-affinity ATP-site inhibitor of FAK. Protein crystallography revealed the binding mode of 41 out of 48 selected fragment hits within the ATP-site. Structural comparison of the fragment binding modes with a DFG-out inhibitor of FAK initiated first synthetic follow-up optimization leading to improved binding affinity.


  • Organizational Affiliation

    Merck KGaA, Merck Serono Research, Darmstadt, Germany. ulrich.graedler@merckgroup.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Focal adhesion kinase 1
A, B
279Homo sapiensMutation(s): 0 
Gene Names: FAKFAK1PTK2
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q05397 (Homo sapiens)
Explore Q05397 
Go to UniProtKB:  Q05397
PHAROS:  Q05397
GTEx:  ENSG00000169398 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ05397
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
K8A
Query on K8A

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
3-bromo-5-(2H-tetrazol-5-yl)pyridine
C6 H4 Br N5
XJGDASCALCDOQH-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
K8A PDBBind:  4K8A Kd: 9.50e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.91 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.184 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.07α = 90
b = 88.559β = 90
c = 137.087γ = 90
Software Package:
Software NamePurpose
XDSdata scaling
MOLREPphasing
BUSTERrefinement
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-11
    Type: Initial release
  • Version 1.1: 2013-10-09
    Changes: Database references
  • Version 1.2: 2023-12-27
    Changes: Data collection, Database references, Derived calculations