4MF1

ITK kinase domain in complex with benzothiazole inhibitor 12b (1S,2S)-2-{4-[(DIMETHYLAMINO)METHYL]PHENYL}-N-[6-(1H-PYRAZOL-4-YL)-1,3-BENZOTHIAZOL-2-YL]CYCLOPROPANECARBOXAMIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).

Mackinnon, C.H.Lau, K.Burch, J.D.Chen, Y.Dines, J.Ding, X.Eigenbrot, C.Heifetz, A.Jaochico, A.Johnson, A.Kraemer, J.Kruger, S.Krulle, T.M.Liimatta, M.Ly, J.Maghames, R.Montalbetti, C.A.Ortwine, D.F.Perez-Fuertes, Y.Shia, S.Stein, D.B.Trani, G.Vaidya, D.G.Wang, X.Bromidge, S.M.Wu, L.C.Pei, Z.

(2013) Bioorg Med Chem Lett 23: 6331-6335

  • DOI: https://doi.org/10.1016/j.bmcl.2013.09.069
  • Primary Citation of Related Structures:  
    4MF0, 4MF1

  • PubMed Abstract: 

    Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.


  • Organizational Affiliation

    Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ITK/TSK
A, B
266Homo sapiensMutation(s): 3 
Gene Names: EMTITKLYK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q08881 (Homo sapiens)
Explore Q08881 
Go to UniProtKB:  Q08881
PHAROS:  Q08881
GTEx:  ENSG00000113263 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08881
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
29Y
Query on 29Y

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(1S,2S)-2-{4-[(dimethylamino)methyl]phenyl}-N-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
C23 H23 N5 O S
WIUYFJQWJMBTCE-MOPGFXCFSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
29Y BindingDB:  4MF1 Ki: min: 0.6, max: 0.7 (nM) from 2 assay(s)
IC50: min: 89, max: 91 (nM) from 2 assay(s)
Binding MOAD:  4MF1 Ki: 0.7 (nM) from 1 assay(s)
PDBBind:  4MF1 Ki: 0.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.842α = 99.01
b = 51.745β = 104.62
c = 66.199γ = 92.31
Software Package:
Software NamePurpose
BOSdata collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-11-13
    Type: Initial release
  • Version 1.1: 2013-11-20
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations