7AK3

CLK1 bound with CAF052

7AK3 の概要

• エントリーDOI: 10.2210/pdb7ak3/pdb
• 分子名称: Dual specificity protein kinase CLK1, ~{N}-[3-fluoranyl-4-(4-methylpiperazin-1-yl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-pyrimidin-2-amine (3 entities in total)
• 機能のキーワード: clk1, kinase, inhibitor, structural genomics, structural genomics consortium, sgc, transferase
• 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: 39985.96

構造登録者

Schroeder, M.,Chaikuad, A.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2020-09-29, 公開日: 2020-11-11, 最終更新日: 2024-01-31)

主引用文献

Schroder, M.,Filippakopoulos, P.,Schwalm, M.P.,Ferrer, C.A.,Drewry, D.H.,Knapp, S.,Chaikuad, A.
Crystal Structure and Inhibitor Identifications Reveal Targeting Opportunity for the Atypical MAPK Kinase ERK3.
Int J Mol Sci, 21:-, 2020

PubMed Abstract: Extracellular signal-regulated kinase 3 (ERK3), known also as mitogen-activated protein kinase 6 (MAPK6), is an atypical member of MAPK kinase family, which has been poorly studied. Little is known regarding its function in biological processes, yet this atypical kinase has been suggested to play important roles in the migration and invasiveness of certain cancers. The lack of tools, such as a selective inhibitor, hampers the study of ERK3 biology. Here, we report the crystal structure of the kinase domain of this atypical MAPK kinase, providing molecular insights into its distinct ATP binding pocket compared to the classical MAPK ERK2, explaining differences in their inhibitor binding properties. Medium-scale small molecule screening identified a number of inhibitors, several of which unexpectedly exhibited remarkably high inhibitory potencies. The crystal structure of CLK1 in complex with CAF052, one of the most potent inhibitors identified for ERK3, revealed typical type-I binding mode of the inhibitor, which by structural comparison could likely be maintained in ERK3. Together with the presented structural insights, these diverse chemical scaffolds displaying both reversible and irreversible modes of action, will serve as a starting point for the development of selective inhibitors for ERK3, which will be beneficial for elucidating the important functions of this understudied kinase.

PubMed: 33114754
DOI: 10.3390/ijms21217953

実験手法

X-RAY DIFFRACTION (2.5 Å)