6GES

Crystal structure of ERK1 covalently bound to SM1-71

6GES の概要

• エントリーDOI: 10.2210/pdb6ges/pdb
• 関連するPDBエントリー: 6G54
• 分子名称: Mitogen-activated protein kinase 3, N-{2-[(5-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]phenyl}propanamide, ~{N}-[2-[[5-chloranyl-2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide, ... (6 entities in total)
• 機能のキーワード: kinase, covalent inhibitor, mapk, 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: 2
• 化学式量合計: 88453.52

構造登録者

Chaikuad, A.,Suman, R.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Gray, N.S.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2018-04-27, 公開日: 2019-02-27, 最終更新日: 2024-01-17)

主引用文献

Rao, S.,Gurbani, D.,Du, G.,Everley, R.A.,Browne, C.M.,Chaikuad, A.,Tan, L.,Schroder, M.,Gondi, S.,Ficarro, S.B.,Sim, T.,Kim, N.D.,Berberich, M.J.,Knapp, S.,Marto, J.A.,Westover, K.D.,Sorger, P.K.,Gray, N.S.
Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome.
Cell Chem Biol, 26:818-, 2019

PubMed Abstract: Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development.

PubMed: 30982749
DOI: 10.1016/j.chembiol.2019.02.021

実験手法

X-RAY DIFFRACTION (2.07 Å)