Evaluation of Cooperative Binding of Histone Post-Translational Modifications and the Surrounding Sequence by Trimethyllysine Reader Proteins.

ABSTRACT: Histone trimethyllysine (Kme3) reader proteins are emerging therapeutic targets. However, development of selective inhibitors has proven challenging given the conserved nature of the aromatic cage which binds Kme3 as well as the myriad reader proteins which bind Kme3 at the same position on histone tails. These readers rely on both the presence of Kme3 as well as the appropriate surrounding histone tail sequence to bind, suggesting that binding is highly cooperative. We recently found that a small subset of Kme3 readers bind with equal or tighter affinity to histone tail peptides which replace Kme3 with its neutral isostere, tBuNle. This unexpected result offers promise for therapeutic design. Herein, we utilize histone 3 tail peptides containing Kme3 or the unnatural tBuNle to probe coope

SUBMITTER: Travis CR 

PROVIDER: S-EPMC12721918 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature