4FVP: Crystal Structure Of The Jak2 Pseudokinase Domain (Apo Form)

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 alpha-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.
PDB ID: 4FVPDownload
MMDB ID: 101530
PDB Deposition Date: 2012/6/29
Updated in MMDB: 2012/08
Experimental Method:
x-ray diffraction
Resolution: 2.01  Å
Source Organism:
Similar Structures:
Biological Unit for 4FVP: monomeric; determined by author and by software (PISA)
Molecular Components in 4FVP
Label Count Molecule
Protein (1 molecule)
Tyrosine-protein Kinase Jak2(Gene symbol: JAK2)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

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