8PSW

ERK2 covalently bound to RU67 cyclohexenone based inhibitor

8PSW の概要

• エントリーDOI: 10.2210/pdb8psw/pdb
• 分子名称: Mitogen-activated protein kinase 1, AMP PHOSPHORAMIDATE, ~{O}3-~{tert}-butyl ~{O}1-methyl (1~{R},3~{R})-4-oxidanylidene-1-(phenylmethyl)cyclohexane-1,3-dicarboxylate, ... (4 entities in total)
• 機能のキーワード: mapk kinase, mapk, inhibitor, covalent, erk2, michael acceptor warhead, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42519.57

構造登録者

Sok, P.,Poti, A.,Remenyi, A.,Gogl, G. (登録日: 2023-07-13, 公開日: 2024-07-24, 最終更新日: 2024-10-16)

主引用文献

Poti, A.L.,Balint, D.,Alexa, A.,Sok, P.,Ozsvath, K.,Albert, K.,Turczel, G.,Magyari, S.,Ember, O.,Papp, K.,Kiraly, S.B.,Imre, T.,Nemeth, K.,Kurtan, T.,Gogl, G.,Varga, S.,Soos, T.,Remenyi, A.
Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold.
Nat Commun, 15:8607-8607, 2024

PubMed Abstract: For mitogen-activated protein kinases (MAPKs) a shallow surface-distinct from the substrate binding pocket-called the D(ocking)-groove governs partner protein binding. Screening of broad range of Michael acceptor compounds identified a double-activated, sterically crowded cyclohexenone moiety as a promising scaffold. We show that compounds bearing this structurally complex chiral warhead are able to target the conserved MAPK D-groove cysteine via reversible covalent modification and interfere with the protein-protein interactions of MAPKs. The electronic and steric properties of the Michael acceptor can be tailored via different substitution patterns. The inversion of the chiral center of the warhead can reroute chemical bond formation with the targeted cysteine towards the neighboring, but less nucleophilic histidine. Compounds bind to the shallow MAPK D-groove with low micromolar affinity in vitro and perturb MAPK signaling networks in the cell. This class of chiral, cyclic and enhanced 3D shaped Michael acceptor scaffolds offers an alternative to conventional ATP-competitive drugs modulating MAPK signaling pathways.

PubMed: 39366929
DOI: 10.1038/s41467-024-52574-1

実験手法

X-RAY DIFFRACTION (2 Å)