7b10
Crystal structure of MLLT1 YEATS domain T1 mutant in complex with benzimidazole-amide based compound 1
Structural highlights
DiseaseENL_HUMAN A chromosomal aberration involving MLLT1 is associated with acute leukemias. Translocation t(11;19)(q23;p13.3) with KMT2A/MLL1. The result is a rogue activator protein. FunctionENL_HUMAN Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.[1] [2] Publication Abstract from PubMedDysfunction 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. Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants.,Ni X, Londregan AT, Owen DR, Knapp S, Chaikuad A ACS Chem Biol. 2021 Mar 21. doi: 10.1021/acschembio.0c00960. PMID:33749253[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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