4QTB

Structure of human ERK1 in complex with SCH772984 revealing a novel inhibitor-induced binding pocket

4QTB の概要

• エントリーDOI: 10.2210/pdb4qtb/pdb
• 関連するPDBエントリー: 4QTA 4QTC 4QTD 4QTE
• 分子名称: Mitogen-activated protein kinase 3, 1,2-ETHANEDIOL, DIMETHYL SULFOXIDE, ... (7 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: P27361
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 89504.72

構造登録者

Chaikuad, A.,Keates, T.,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 (1.4 Å)