2. Academic Validation
  3. Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5

Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5

  • Nat Chem Biol. 2026 Jan 8. doi: 10.1038/s41589-025-02099-5.
F Wieland Goetzke 1,  Steffen M Bernard 2,  Cheng-Wei Ju 3 4 5,  Jonathan Pollock 2,  Kristen E DeMeester 6,  Jacob Gross 2,  Gabriel M Simon 2,  Chuan He 3 4 7,  Bruno Melillo 8,  Benjamin F Cravatt 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Scripps Research, La Jolla, CA, USA. fgoetzke@scripps.edu.
  • 2 Vividion Therapeutics, San Diego, CA, USA.
  • 3 Department of Chemistry, The University of Chicago, Chicago, IL, USA.
  • 4 Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
  • 5 Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL, USA.
  • 6 Department of Chemistry, Scripps Research, La Jolla, CA, USA.
  • 7 Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA.
  • 8 Department of Chemistry, Scripps Research, La Jolla, CA, USA. bmelillo@scripps.edu.
  • 9 Department of Chemistry, Scripps Research, La Jolla, CA, USA. cravatt@scripps.edu.
PMID: 41507545 DOI: 10.1038/s41589-025-02099-5
Abstract

Adaptors serve as hubs to regulate diverse protein complexes in cells. This multitude of functions can complicate the study of adaptors, as their genetic disruption may simultaneously impair the activities of several compositionally distinct complexes (or adaptor 'complexoforms'). Here we describe the chemical proteomic discovery of bicyclopyrrolidine acrylamide stereoprobes that react with C100 of the methyltransferase (MT) adaptor TRMT112 in human cells. Curiously, the stereoprobes showed negligible reactivity with uncomplexed recombinant TRMT112 and we found that this interaction was restored exclusively in the presence of METTL5 but not Other MTs. A cocrystal structure revealed stereoprobe binding to a composite pocket proximal to C100 of TRMT112 that is templated by METTL5 and absent in Other TRMT112:MT complexes. Structural rearrangements promoted by stereoprobe binding in turn lead to allosteric agonism of METTL5, thus revealing how covalent ligands targeting a pleiotropic adaptor can confer partner-specific functional effects through reactivity with a single complexoform.

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