Download MendeleyStructure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants.
Ni, X., Londregan, A.T., Owen, D.R., Knapp, S., Chaikuad, A.(2021) ACS Chem Biol 16: 571-578
- PubMed: 33749253
- DOI: https://doi.org/10.1021/acschembio.0c00960
- Primary Citation of Related Structures:
7B0T, 7B10 - PubMed Abstract:
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.
Organizational Affiliation:
Structural Genomics Consortium and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Stra?e 15, 60438 Frankfurt am Main, Germany.
