8PT5
ERK2 covelently bound to RU187 cyclohexenone based inhibitor
Summary for 8PT5
| Entry DOI | 10.2210/pdb8pt5/pdb |
| Descriptor | Mitogen-activated protein kinase 1, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ~{O}3-~{tert}-butyl ~{O}1-methyl (1~{S},3~{R})-1-methyl-4-oxidanylidene-cyclohexane-1,3-dicarboxylate, ... (5 entities in total) |
| Functional Keywords | mapk kinase, mapk, inhibitor, covalent, erk2, signaling protein, michael acceptor warhead |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 42615.55 |
| Authors | Sok, P.,Poti, A.,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 Cited by 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: 39366929DOI: 10.1038/s41467-024-52574-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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