Activity-based protein profiling facilitated the discovery of complexation state-selective covalent ligands for the pleiotropic methyltransferase adaptor TRMT112. Structural studies revealed that these ligands bind to a pocket at the interface of TRMT112 and METTL5 that is absent in other TRMT112–methyltransferase complexes, resulting in allosteric potentiation of METTL5-mediated rRNA methylation.
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References
Aebersold, R. et al. How many human proteoforms are there?. Nat. Chem. Biol. 14, 206–214 (2018). A perspective article that calls attention to the remarkable complexity of the human proteome achieved through post-transcriptional and post-translational mechanisms.
Gomes, F. P. et al. Native top-down proteomics enables discovery in endocrine-resistant breast cancer. Nat. Chem. Biol. 21, 1205–1213 (2025). This paper presents a global intact mass spectrometry-based characterization of complexoforms in human cells.
Niphakis, M. J. & Cravatt, B. F. Ligand discovery by activity-based protein profiling. Cell Chem. Biol. 31, 1636–1651 (2024). A review article that describes how ABPP technologies enable chemical probe and drug development.
Njomen, E. et al. Multi-tiered chemical proteomic maps of tryptoline acrylamide–protein interactions in cancer cells. Nat. Chem. 16, 1592–1604 (2024). This paper presents a general protein-directed ABPP workflow for mapping protein-ligand interactions, which was crucial for identifying the complexoform-restricted liganding event in this study.
Turkalj, E. M. & Vissers, C. The emerging importance of METTL5-mediated ribosomal RNA methylation. Exp. Mol. Med. 54, 1617–1625 (2022). A review article that summarizes the current understanding of the role of METTL5 in ribosome function.
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This is a summary of: Goetzke, F. W. et al. Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5. Nat. Chem. Biol. https://doi.org/10.1038/s41589-025-02099-5 (2026).
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Complexoform-specific ligands that modulate the pleiotropic methyltransferase adaptor TRMT112. Nat Chem Biol (2026). https://doi.org/10.1038/s41589-025-02125-6
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DOI: https://doi.org/10.1038/s41589-025-02125-6
