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bioRxiv · 10.1101/2021.02.08.430291

Structure and inhibitor binding characterization of oncogenic MLLT1 mutants

Ni, X.·Londregan, A. T.·Owen, D. R.·Knapp, S.·Chaikuad, A.
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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, 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.

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Ni, X., Londregan, A. T., Owen, D. R., Knapp, S., Chaikuad, A.. 2021-02-08. Structure and inhibitor binding characterization of oncogenic MLLT1 mutants. https://doi.org/10.1101/2021.02.08.430291

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