Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants

• Published in: ACS chemical biology Vol. 16; no. 4; pp. 571 - 578
• Main Authors: Ni, Xiaomin, Londregan, Allyn T, Owen, Dafydd R, Knapp, Stefan, Chaikuad, Apirat
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.04.2021
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.0c00960

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