Browse by author
Lookup NU author(s): Professor Steven CliffordORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Neomorphic mutations and drugs can elicit unanticipated effects that require mechanistic understanding to inform clinical practice. Recurrent indel mutations in the Kelch domain of the KBTBD4 E3 ligase rewire epigenetic programs for stemness in medulloblastoma by recruiting LSD1-CoREST-HDAC1/2 complexes as neo-substrates for ubiquitination and degradation. UM171, an investigational drug for haematopoietic stem cell transplantation, was found to degrade LSD1-CoREST-HDAC1/2 complexes in a wild-type KBTBD4-dependent manner, suggesting a potential common mode of action. Here, we identify that these neomorphic interactions are mediated by the HDAC deacetylase domain. Cryo-EM studies of both wild-type and mutant KBTBD4 capture 2:1 and 2:2 KBTBD4-HDAC2 complexes, as well as a 2:1:1 KBTBD4-HDAC2-CoREST1 complex, at resolutions spanning 2.7 to 3.3 Å. The mutant and drug-induced complexes adopt similar structural assemblies requiring both Kelch domains in the KBTBD4 dimer for each HDAC2 interaction. UM171 is identified as a bona fide molecular glue binding across the ternary interface. Most strikingly, the indel mutation reshapes the same surface of KBTBD4 providing an example of a natural mimic of a molecular glue. Together, the structures provide mechanistic understanding of neomorphic KBTBD4, while structure-activity relationship (SAR) analysis of UM171 reveals analog S234984 as a more potent molecular glue for future studies.
Author(s): Chen Z, Chi G, Balo T, Chen X, Montes BR, Clifford SC, D'Angiolella V, Szabo T, Kiss A, Novak T, Herner A, Kotschy A, Bullock AN
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Issue: 1
Online publication date: 02/04/2025
Acceptance date: 20/03/2025
Date deposited: 15/04/2025
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-025-58350-z
DOI: 10.1038/s41467-025-58350-z
Data Access Statement: Data availability Cryo-EM maps and atomic coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) under accession codes EMD-51337 and PDB 9GGM (2:2 KBTBD4R313PRRHDAC2), EMD-51338 and PDB 9GGN (2:2 KBTBD4WT-HDAC2 with UM171), EMD-51335 and PDB 9GGL (2:1 KBTBD4WT-HDAC2 with UM171) as well as EMD-51336 and PDB 9I2C<(2:1:1 KBTBD4WT-HDAC2-CoREST1 with UM171). All other data are available in the manuscript or the supplementary materials. Further information and requests for resources and reagents should be directed to and will be fulfilled by the corresponding author. Source data are provided with this paper.
Altmetrics provided by Altmetric
