Allele-Specific Chemical Rescue of Histone Demethylases Using Abiotic Cofactors.

ABSTRACT: Closely related protein families evolved from common ancestral genes present a significant hurdle in developing member- and isoform-specific chemical probes, owing to their similarity in fold and function. In this piece of work, we explore an allele-specific chemical rescue strategy to activate a "dead" variant of a wildtype protein using synthetic cofactors and demonstrate its successful application to the members of the alpha-ketoglutarate (αKG)-dependent histone demethylase 4 (KDM4) family. We show that a mutation at a specific residue in the catalytic site renders the variant inactive toward the natural cosubstrate. In contrast, αKG derivatives bearing appropriate stereoelectronic features endowed the mutant with native-like demethylase activity while remaining refractory to a set of w

SUBMITTER: Scott V 

PROVIDER: S-EPMC10230450 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature