7UP7

Crystal structure of C-terminal Domain of MSK1 in complex with covalently bound with literature RSK2 inhibitor indazole cyanoacrylamide compound 26 (soak)

7UP7 の概要

• エントリーDOI: 10.2210/pdb7up7/pdb
• 分子名称: Ribosomal protein S6 kinase alpha-5, (2S)-2-cyano-N-(1-hydroxy-2-methylpropan-2-yl)-3-[3-(3,4,5-trimethoxyphenyl)-1H-indazol-5-yl]propanamide (3 entities in total)
• 機能のキーワード: protein kinase, transferase, phosphorylation, 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: 2
• 化学式量合計: 70242.62

構造登録者

Yano, J.K.,Abendroth, J.,Hall, A. (登録日: 2022-04-14, 公開日: 2022-07-20, 最終更新日: 2024-10-30)

主引用文献

Hall, A.,Abendroth, J.,Bolejack, M.J.,Ceska, T.,Dell'Aiera, S.,Ellis, V.,Fox 3rd, D.,Francois, C.,Muruthi, M.M.,Prevel, C.,Poullennec, K.,Romanov, S.,Valade, A.,Vanbellinghen, A.,Yano, J.,Geraerts, M.
Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.
Acs Med.Chem.Lett., 13:1099-1108, 2022

PubMed Abstract: We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an SAr reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by biochemical experiments and was confirmed by mass spectrometry. Ultimately, the displacement of the 2-chloro moiety was confirmed by crystallization of an inhibitor with the CTKD. We also disclose the crystal structures of three compounds from this series bound to the CTKD of MSK1, in addition to the crystal structures of two unrelated RSK2 covalent inhibitors bound to the CTKD of MSK1.

PubMed: 35859861
DOI: 10.1021/acsmedchemlett.2c00134

実験手法

X-RAY DIFFRACTION (2.8 Å)