5I4N

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

Summary for 5I4N

• Entry DOI: 10.2210/pdb5i4n/pdb
• Descriptor: Tyrosine-protein kinase JAK2, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: transferase, pseudokinase, atp binding
• Biological source: Homo sapiens (Human)
• Cellular location: Endomembrane system ; Peripheral membrane protein : O60674
• Total number of polymer chains: 1
• Total formula weight: 33865.74

Authors

Shiau, A.K.,Motamedi, A. (deposition date: 2016-02-12, release date: 2016-04-13, Last modification date: 2023-09-27)

Primary citation

Leroy, E.,Dusa, A.,Colau, D.,Motamedi, A.,Cahu, X.,Mouton, C.,Huang, L.J.,Shiau, A.K.,Constantinescu, S.N.
Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 alpha C helix.
Biochem.J., 473:1579-1591, 2016

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.

PubMed: 27029346
DOI: 10.1042/BCJ20160085

Experimental method

X-RAY DIFFRACTION (1.54 Å)