PT  - JOURNAL ARTICLE
AU  - Xiaomin Ni
AU  - Allyn T. Londregan
AU  - Dafydd R. Owen
AU  - Stefan Knapp
AU  - Apirat Chaikuad
TI  - Structure and inhibitor binding characterization of oncogenic MLLT1 mutants
AID  - 10.1101/2021.02.08.430291
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.08.430291
4099  - http://biorxiv.org/content/early/2021/02/08/2021.02.08.430291.short
4100  - http://biorxiv.org/content/early/2021/02/08/2021.02.08.430291.full
AB  - 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.Competing Interest StatementAllyn T. Londregan and Dafydd R. Owen are employees of Pfizer.YEATS domainThe Yaf9, ENL, AF9, Taf14, Sas5 (YEATS) domain;ENLeleven-nineteen-leukemia protein;MLLT1myeloid/lymphoid or mixed-lineage leukemia translocated to, chromosome 1 protein;AF9ALL1-fused gene from chromosome 9 protein;MLLT3myeloid/lymphoid or mixed-lineage leukemia translocated to chromosome 3 protein.