5I4N

Crystal Structure of the E596A V617F Mutant JAK2 Pseudokinase Domain Bound to Mg-ATP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.54 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.174 

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This is version 1.2 of the entry. See complete history


Literature

Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 alpha C helix.

Leroy, E.Dusa, A.Colau, D.Motamedi, A.Cahu, X.Mouton, C.Huang, L.J.Shiau, A.K.Constantinescu, S.N.

(2016) Biochem J 473: 1579-1591

  • DOI: https://doi.org/10.1042/BCJ20160085
  • Primary Citation of Related Structures:  
    5I4N

  • PubMed Abstract: 

    The mechanisms by which JAK2 is activated by the prevalent pseudokinase (JH2) V617F mutation in blood cancers remain elusive. Via structure-guided mutagenesis and transcriptional and functional assays, we identify a community of residues from the JH2 helix αC, SH2-JH2 linker and JH1 kinase domain that mediate V617F-induced activation. This circuit is broken by altering the charge of residues along the solvent-exposed face of the JH2 αC, which is predicted to interact with the SH2-JH2 linker and JH1. Mutations that remove negative charges or add positive charges, such as E596A/R, do not alter the JH2 V617F fold, as shown by the crystal structure of JH2 V617F E596A. Instead, they prevent kinase domain activation via modulation of the C-terminal residues of the SH2-JH2 linker. These results suggest strategies for selective V617F JAK2 inhibition, with preservation of wild-type function.


  • Organizational Affiliation

    Ludwig Institute for Cancer Research, 1200 Brussels, Belgium de Duve Institute, Université catholique de Louvain, 1200 Brussels, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2290Homo sapiensMutation(s): 5 
Gene Names: JAK2
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for O60674 (Homo sapiens)
Explore O60674 
Go to UniProtKB:  O60674
PHAROS:  O60674
GTEx:  ENSG00000096968 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60674
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.54 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.174 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.429α = 90
b = 56.965β = 90
c = 114.868γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-13
    Type: Initial release
  • Version 1.1: 2016-06-08
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description