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.
Author: | Xiaomin NiORCiDGND, Allyn T. LondreganORCiD, Dafydd R. OwenORCiD, Stefan KnappORCiD, Apirat ChaikuadORCiD |
---|---|
URN: | urn:nbn:de:hebis:30:3-728601 |
DOI: | https://doi.org/10.1101/2021.02.08.430291 |
Parent Title (English): | bioRxiv |
Document Type: | Preprint |
Language: | English |
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 |
Issue: | 2021.02.08.430291 |
Page Number: | 16 |
HeBIS-PPN: | 509407927 |
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 |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International |