Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1
journal contributionposted on 2019-12-02, 22:03 authored by Xiaomin Ni, David Heidenreich, Thomas Christott, James Bennett, Moses Moustakim, Paul E. Brennan, Oleg Fedorov, Stefan Knapp, Apirat Chaikuad
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.
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Alternative Piperazine-urea YEATS Domain BindersMLLT 1 YEATS-domain-containing MLLT 1well-studied bromodomainsbinding pocketsInteraction MechanismsYEATS domain familyMLLT 1. Crystal structurespiperazine-urea derivativespiperazine-urea scaffoldacetylStructural Insightsinteraction mechanismsalternative strategy