Structure and inhibitor binding characterization of oncogenic MLLT1 mutants

  • 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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Author:Xiaomin NiORCiDGND, Allyn T. LondreganORCiD, Dafydd R. OwenORCiD, Stefan KnappORCiD, Apirat ChaikuadORCiD
Parent Title (English):bioRxiv
Document Type:Preprint
Date of Publication (online):2021/02/08
Date of first Publication:2021/02/08
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/06/22
Page Number:16
Institutes:Biochemie, Chemie und Pharmazie
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International