4QYY

Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase State

4QYY の概要

• エントリーDOI: 10.2210/pdb4qyy/pdb
• 分子名称: Mitogen-activated protein kinase 1, (3R)-1-{2-[4-(4-acetylphenyl)piperazin-1-yl]-2-oxoethyl}-N-(3-chloro-4-hydroxyphenyl)pyrrolidine-3-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: transferase, serine/threonine-protein kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Rattus norvegicus (brown rat,rat,rats)
• 細胞内の位置: Cytoplasm, cytoskeleton, spindle : P63086
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43003.67

構造登録者

Deng, Y.,Shipps, G.W.,Cooper, A.,English, J.M.,Annis, D.A.,Carr, D.,Nan, Y.,Wang, T.,Zhu, Y.H.,Chuang, C.,Dayananth, P.,Hruza, A.W.,Xiao, L.,Jin, W.,Kirschmeier, P.,Windsor, W.T.,Samatar, A.A. (登録日: 2014-07-26, 公開日: 2014-11-12, 最終更新日: 2023-09-20)

主引用文献

Deng, Y.,Shipps, G.W.,Cooper, A.,English, J.M.,Annis, D.A.,Carr, D.,Nan, Y.,Wang, T.,Zhu, H.Y.,Chuang, C.C.,Dayananth, P.,Hruza, A.W.,Xiao, L.,Jin, W.,Kirschmeier, P.,Windsor, W.T.,Samatar, A.A.
Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase.
J.Med.Chem., 57:8817-8826, 2014

PubMed Abstract: An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound 4 to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which 4 can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity.

PubMed: 25313996
DOI: 10.1021/jm500847m

実験手法

X-RAY DIFFRACTION (1.65 Å)