4FVQ

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

Summary for 4FVQ

• Entry DOI: 10.2210/pdb4fvq/pdb
• Related: 4FVP 4FVR
• Descriptor: Tyrosine-protein kinase JAK2, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: janus protein kinase, pseudokinase, atp binding, phosphorylation, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system ; Peripheral membrane protein : O60674
• Total number of polymer chains: 1
• Total formula weight: 33770.54

Authors

Bandaranayake, R.M.,Hubbard, S.R. (deposition date: 2012-06-29, release date: 2012-07-25, Last modification date: 2023-09-13)

Primary citation

Bandaranayake, R.M.,Ungureanu, D.,Shan, Y.,Shaw, D.E.,Silvennoinen, O.,Hubbard, S.R.
Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F.
Nat.Struct.Mol.Biol., 19:754-759, 2012

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.

PubMed: 22820988
DOI: 10.1038/nsmb.2348

Experimental method

X-RAY DIFFRACTION (1.75 Å)