Structural Genomics Consortium and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.
ACS Chem Biol. 2021 Apr 16;16(4):571-578. doi: 10.1021/acschembio.0c00960. Epub 2021 Mar 21.
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, 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.
YEATS 结构域包含的 MLLT1 功能障碍，一种乙酰化/酰化赖氨酸依赖的表观遗传读取域，与侵袭性癌症的发生有关。最近报道 YEATS 结构域的突变是导致 MLLT1 异常读取功能的原因。然而，报道的亲和力改变的乙酰化/酰化组蛋白的结构基础仍然难以捉摸。在这里，我们报告了存在于癌症中的插入和取代突变体的晶体结构，揭示了 YEATS 结构域环 8 的显著构象变化。结构比较表明，这种改变不仅改变了与乙酰化/酰化组蛋白的结合界面，而且 T1 突变体中环中的序列改变可能允许二聚体组装，这与诱导自缔合行为一致。然而，我们还表明，开发的乙酰赖氨酸模拟抑制剂也可以靶向 MLLT1 突变体，其亲和力与野生型相似。我们的报告为改变的行为提供了结构基础，并为靶向致癌 MLLT1 突变体提供了一种潜在的策略。
