4QTE

Structure of ERK2 in complex with VTX-11e, 4-{2-[(2-CHLORO-4-FLUOROPHENYL)AMINO]-5-METHYLPYRIMIDIN-4-YL}-N-[(1S)-1-(3-CHLOROPHENYL)-2-HYDROXYETHYL]-1H-PYRROLE-2-CARBOXAMIDE

4QTE の概要

• エントリーDOI: 10.2210/pdb4qte/pdb
• 関連するPDBエントリー: 4QTA 4QTB 4QTC 4QTD
• 分子名称: Mitogen-activated protein kinase 1, 1,2-ETHANEDIOL, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: structural genomics, structural genomics consortium, sgc, transferase, kinase, mapk, signalling, inhibitor, allosteric, structural genomics consortium (sgc), transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, spindle (By similarity): P28482
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43948.80

構造登録者

Chaikuad, A.,Savitsky, P.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2014-07-07, 公開日: 2014-07-23, 最終更新日: 2023-09-20)

主引用文献

Chaikuad, A.,M C Tacconi, E.,Zimmer, J.,Liang, Y.,Gray, N.S.,Tarsounas, M.,Knapp, S.
A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
Nat.Chem.Biol., 10:853-860, 2014

PubMed Abstract: Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.

PubMed: 25195011
DOI: 10.1038/nchembio.1629

実験手法

X-RAY DIFFRACTION (1.5 Å)