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Crystal Structures of the JAK2 Pseudokinase Domain and the Pathogenic Mutant V617F

Crystal Structures of the JAK2 Pseudokinase Domain and the Pathogenic Mutant V617F

Rajintha M Bandaranayake, Daniela Ungureanu, Yibing Shan, David E Shaw, Olli Silvennoinen, Stevan R Hubbard

Nat Struct Mol Biol. 2012 Aug;19(8):754-9.

PMID: 22820988

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416389	Jak2 Jh1 Active human			Price

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