3PJC

Crystal structure of JAK3 complexed with a potent ATP site inhibitor showing high selectivity within the Janus kinase family

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

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This is version 1.3 of the entry. See complete history. 


Literature

Identification of a Potent Janus Kinase 3 Inhibitor with High Selectivity within the Janus Kinase Family.

Thoma, G., Nuninger, F., Falchetto, R., Hermes, E., Tavares, G.A., Vangrevelinghe, E., Zerwes, H.G.

(2011) J Med Chem 54: 284-288

  • DOI: https://doi.org/10.1021/jm101157q
  • Primary Citation of Related Structures:  
    3PJC

  • PubMed Abstract: 

    We describe a synthetic approach toward the rapid modification of phenyl-indolyl maleimides and the discovery of potent Jak3 inhibitor 1 with high selectivity within the Jak kinase family. We provide a rationale for this unprecedented selectivity based on the X-ray crystal structure of an analogue of 1 bound to the ATP-binding site of Jak3. While equally potent compared to the Pfizer pan Jak inhibitor CP-690,550 (2) in an enzymatic Jak3 assay, compound 1 was found to be 20-fold less potent in cellular assays measuring cytokine-triggered signaling through cytokine receptors containing the common γ chain (γC). Contrary to compound 1, compound 2 inhibited Jak1 in addition to Jak3. Permeability and cellular concentrations of compounds 1 and 2 were similar. As Jak3 always cooperates with Jak1 for signaling, we speculate that specific inhibition of Jak3 is not sufficient to efficiently block γC cytokine signal transduction required for strong immunosuppression.

    • Organizational Affiliation: 

    Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, Basel, Switzerland. gebhard.thoma@novartis.com


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK3315Homo sapiensMutation(s): 0 
Gene Names: JAK3
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P52333 (Homo sapiens)
Explore P52333 
Go to UniProtKB:  P52333
PHAROS:  P52333
GTEx:  ENSG00000105639 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP52333
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PJC
Query on PJC
Download Ideal Coordinates CCD File 
B [auth A]3-(1H-indol-3-yl)-4-[2-(4-oxopiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrrole-2,5-dione
C22 H16 F3 N5 O3
MYIILBMNTUDZDH-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
PJC PDBBind:  3PJC IC50: 27 (nM) from 1 assay(s)
BindingDB:  3PJC IC50: 27 (nM) from 1 assay(s)
Binding MOAD:  3PJC IC50: 27 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.722α = 90
b = 71.991β = 90
c = 107.8γ = 90
Software Package:
Software NamePurpose
PHASERphasing
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-29
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-09-28
    Changes: Database references
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations