8PSR

ERK2 covalently bound to SynthRevD-12-opt artificial peptide

Summary for 8PSR

• Entry DOI: 10.2210/pdb8psr/pdb
• Descriptor: Mitogen-activated protein kinase 1, SynthRevD-12-opt, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• Functional Keywords: mapk kinase, mapk, inhibitor, covalent, erk2, michael acceptor warhead, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 44871.22

Authors

Sok, P.,Poti, A.,Gogl, G.,Remenyi, A. (deposition date: 2023-07-13, release date: 2024-07-24, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)