4JG8

Structure of RSK2 T493M CTD mutant bound to 2-cyano-N-(1-hydroxy-2-methylpropan-2-yl)-3-(3-(3,4,5-trimethoxyphenyl)-1H-indazol-5-yl)acrylamide

4JG8 の概要

• エントリーDOI: 10.2210/pdb4jg8/pdb
• 分子名称: Ribosomal protein S6 kinase alpha-3, (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, phosphorylation, covalent inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : P51812
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40550.15

構造登録者

Miller, R.M.,Paavilainen, V.O.,Krishnan, S.,Serafimova, I.M.,Taunton, J. (登録日: 2013-02-28, 公開日: 2013-04-10, 最終更新日: 2024-11-06)

主引用文献

Miller, R.M.,Paavilainen, V.O.,Krishnan, S.,Serafimova, I.M.,Taunton, J.
Electrophilic fragment-based design of reversible covalent kinase inhibitors.
J.Am.Chem.Soc., 135:5298-5301, 2013

PubMed Abstract: Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine thiols. Using this strategy, we identify electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated to afford 12 (RMM-46), a reversible covalent inhibitor that exhibits high ligand efficiency and selectivity for MSK/RSK-family kinases. At nanomolar concentrations, 12 blocked activation of cellular MSK and RSK, as well as downstream phosphorylation of the critical transcription factor, CREB.

PubMed: 23540679
DOI: 10.1021/ja401221b

実験手法

X-RAY DIFFRACTION (3.1002 Å)