8FE9

Crystal structure of Ack1 kinase K161Q mutant in complex with the selective inhibitor (R)-9b

8FE9 の概要

• エントリーDOI: 10.2210/pdb8fe9/pdb
• 分子名称: Activated CDC42 kinase 1, 5-chloro-N~2~-[4-(4-methylpiperazin-1-yl)phenyl]-N~4~-{[(2R)-oxolan-2-yl]methyl}pyrimidine-2,4-diamine (2 entities in total)
• 機能のキーワード: tyrosine kinase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32897.32

構造登録者

Paung, Y.,Kan, Y.,Seeliger, M.S.,Miller, W.T. (登録日: 2022-12-06, 公開日: 2023-03-29, 最終更新日: 2024-11-20)

主引用文献

Kan, Y.,Paung, Y.,Kim, Y.,Seeliger, M.A.,Miller, W.T.
Biochemical Studies of Systemic Lupus Erythematosus-Associated Mutations in Nonreceptor Tyrosine Kinases Ack1 and Brk.
Biochemistry, 62:1124-1137, 2023

PubMed Abstract: Tyrosine kinases (TKs) play essential roles in signaling processes that regulate cell survival, migration, and proliferation. Dysregulation of tyrosine kinases underlies many disorders, including cancer, cardiovascular and developmental diseases, as well as pathologies of the immune system. Ack1 and Brk are nonreceptor tyrosine kinases (NRTKs) best known for their roles in cancer. Here, we have biochemically characterized novel Ack1 and Brk mutations identified in patients with systemic lupus erythematosus (SLE). These mutations are the first SLE-linked polymorphisms found among NRTKs. We show that two of the mutants are catalytically inactive, while the other three have reduced activity. To understand the structural changes associated with the loss-of-function phenotype, we solved the crystal structure of one of the Ack1 kinase mutants, K161Q. Furthermore, two of the mutated residues (Ack1 A156 and K161) critical for catalytic activity are highly conserved among other TKs, and their substitution in other members of the kinase family could have implications in cancer. In contrast to canonical gain-of-function mutations in TKs observed in many cancers, we report loss-of-function mutations in Ack1 and Brk, highlighting the complexity of TK involvement in human diseases.

PubMed: 36854171
DOI: 10.1021/acs.biochem.2c00685

実験手法

X-RAY DIFFRACTION (3.2 Å)