4FVR

Crystal structure of the Jak2 pseudokinase domain mutant V617F (Mg-ATP-bound form)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F.

Bandaranayake, R.M.Ungureanu, D.Shan, Y.Shaw, D.E.Silvennoinen, O.Hubbard, S.R.

(2012) Nat Struct Mol Biol 19: 754-759

  • DOI: https://doi.org/10.1038/nsmb.2348
  • Primary Citation of Related Structures:  
    4FVP, 4FVQ, 4FVR

  • PubMed Abstract: 

    The protein tyrosine kinase JAK2 mediates signaling through numerous cytokine receptors. JAK2 possesses a pseudokinase domain (JH2) and a tyrosine kinase domain (JH1). Through unknown mechanisms, JH2 regulates the catalytic activity of JH1, and hyperactivating mutations in the JH2 region of human JAK2 cause myeloproliferative neoplasms (MPNs). We showed previously that JAK2 JH2 is, in fact, catalytically active. Here we present crystal structures of human JAK2 JH2, including both wild type and the most prevalent MPN mutant, V617F. The structures reveal that JH2 adopts the fold of a prototypical protein kinase but binds Mg-ATP noncanonically. The structural and biochemical data indicate that the V617F mutation rigidifies α-helix C in the N lobe of JH2, facilitating trans-phosphorylation of JH1. The crystal structures of JH2 afford new opportunities for the design of novel JAK2 therapeutics targeting MPNs.


  • Organizational Affiliation

    Structural Biology Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2289Homo sapiensMutation(s): 3 
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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ATP
Query on ATP

Download Ideal Coordinates CCD File 
B [auth A]ADENOSINE-5'-TRIPHOSPHATE
C10 H16 N5 O13 P3
ZKHQWZAMYRWXGA-KQYNXXCUSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ATP PDBBind:  4FVR Kd: 1000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.9α = 90
b = 57.326β = 111.86
c = 60.555γ = 90
Software Package:
Software NamePurpose
d*TREKdata scaling
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
HKL-3000data reduction
HKL-3000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-07-25
    Type: Initial release
  • Version 1.1: 2012-08-08
    Changes: Database references
  • Version 1.2: 2012-08-22
    Changes: Database references
  • Version 1.3: 2017-11-15
    Changes: Refinement description
  • Version 1.4: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description