4M0Z

Crystal structure of ITK in complex with compound 5 {4-(carbamoylamino)-1-(7-methoxynaphthalen-1-yl)-1H-pyrazole-3-carboxamide}


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.167 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Selectively targeting an inactive conformation of interleukin-2-inducible T-cell kinase by allosteric inhibitors.

Han, S.Czerwinski, R.M.Caspers, N.L.Limburg, D.C.Ding, W.Wang, H.Ohren, J.F.Rajamohan, F.McLellan, T.J.Unwalla, R.Choi, C.Parikh, M.D.Seth, N.Edmonds, J.Phillips, C.Shakya, S.Li, X.Spaulding, V.Hughes, S.Cook, A.Robinson, C.Mathias, J.P.Navratilova, I.Medley, Q.G.Anderson, D.R.Kurumbail, R.G.Aulabaugh, A.

(2014) Biochem J 460: 211-222

  • DOI: https://doi.org/10.1042/BJ20131139
  • Primary Citation of Related Structures:  
    4M0Y, 4M0Z, 4M12, 4M13, 4M14, 4M15

  • PubMed Abstract: 

    ITK (interleukin-2-inducible T-cell kinase) is a critical component of signal transduction in T-cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell-mediated inflammatory diseases. In the present study we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared with the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by steady-state enzyme kinetics. The activity of the isolated kinase domain and auto-activation of the full-length enzyme were inhibited with similar potency. However, inhibition of the activated full-length enzyme was weaker, presumably because the allosteric site is altered when ITK becomes activated. An optimized lead showed exquisite kinome selectivity and is efficacious in human whole blood and proximal cell-based assays.


  • Organizational Affiliation

    *Pfizer Worldwide Research, Eastern Point Road, Groton, CT 06340, U.S.A.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ITK/TSK269Homo sapiensMutation(s): 0 
Gene Names: ITKEMTLYK
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
M0Z
Query on M0Z

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
4-(carbamoylamino)-1-(7-methoxynaphthalen-1-yl)-1H-pyrazole-3-carboxamide
C16 H15 N5 O3
RPIDLPZPJARENN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
M0Z Binding MOAD:  4M0Z Kd: 6400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.167 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.36α = 90
b = 68.77β = 107.02
c = 49.6γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
BUSTERrefinement
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: 2014-04-02
    Type: Initial release
  • Version 1.1: 2014-06-04
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations