5I4N

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

5I4N の概要

• エントリーDOI: 10.2210/pdb5i4n/pdb
• 分子名称: Tyrosine-protein kinase JAK2, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: transferase, pseudokinase, atp binding
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endomembrane system ; Peripheral membrane protein : O60674
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33865.74

構造登録者

Shiau, A.K.,Motamedi, A. (登録日: 2016-02-12, 公開日: 2016-04-13, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.54 Å)