Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling.

ABSTRACT: For targeted covalent modification at low-reactivity carboxylates with biocompatible electrophiles, new approaches are in high demand. Engineering of the HaloTag protein facilitates such a covalent reaction between chloroalkanes and an aspartate residue. We demonstrate that conversely, engineering stable ligands can also enable covalent targeting of an acid residue in a protein binding site. Using the chaperone PDEδ, which shuttles lipidated oncoproteins and thereby mediates their signaling activity, we show that equipping noncovalent inhibitors with a benzyl fluoride-based electrophile leads to covalent modification of a specific glutamate p.E88 in the ligand binding site. The best inhibitor, Deltafluorine, embodies a 3-fluoromethyl-pyridyl group and is stable to nucleophiles like glutath

SUBMITTER: Zhang R 

PROVIDER: S-EPMC12833852 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature