TY  - INPR
A1  - Ni, Xiaomin
A1  - Londregan, Allyn T.
A1  - Owen, Dafydd R.
A1  - Knapp, Stefan
A1  - Chaikuad, Apirat
T1  - Structure and inhibitor binding characterization of oncogenic MLLT1 mutants
T2  - bioRxiv
N2  - 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, structural basis for the reported alterations in affinity for acetyled/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that such alteration not only altered the binding interface for acetylated/acylated histones, but the sequence alterations in the T1 loop may enable dimeric assembly consistent 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 potential strategy for targeting oncogenic MLLT1 mutants.
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/72860
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-728601
IS  - 2021.02.08.430291
ER  -