Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants

Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development aggressive cancers. Mutations YEATS domain have recently reported as a cause MLLT1 aberrant function. However, structural basis for alterations affinity acetylated/acylated histone remained elusive. Here, we report crystal structures both insertion and substitution mutants present cancer, revealing significant conformational changes YEATS-domain loop 8. Structural comparison demonstrates that not only did such alteration alter binding interface histones, but sequence T1 mutant may enable dimeric assembly consistent with inducing self-association behavior. Nevertheless, show also can be targeted by developed acetyllysine mimetic inhibitors affinities similarly to wild-type. Our provides altered behaviors potential strategy targeting oncogenic mutants.