2. Academic Validation
  3. Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants

Structure and Inhibitor Binding Characterization of Oncogenic MLLT1 Mutants

  • ACS Chem Biol. 2021 Apr 16;16(4):571-578. doi: 10.1021/acschembio.0c00960.
Xiaomin Ni 1 2,  Allyn T Londregan 3,  Dafydd R Owen 4,  Stefan Knapp 1 2 5,  Apirat Chaikuad 1 2
Affiliations

Affiliations

  • 1 Structural Genomics Consortium and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
  • 2 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.
  • 3 Medicine Design, Pfizer Worldwide Research Development and Medicine, Eastern Point Road, Groton, Connecticut 06340, United States.
  • 4 Medicine Design, Pfizer Worldwide Research Development and Medicine, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 5 German Cancer network DKTK and Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, 60596 Frankfurt am Main, Germany.
PMID: 33749253 DOI: 10.1021/acschembio.0c00960
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, 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.

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