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Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5
F Wieland Goetzke1, Steffen M Bernard2, Cheng-Wei Ju3,4,5
1Department of Chemistry, Scripps Research, La Jolla, CA, USA. fgoetzke@scripps.edu.
Nature Chemical Biology
|January 8, 2026
Summary
Researchers developed chemical probes to specifically target the TRMT112 adaptor protein when it interacts with METTL5. This approach allows for partner-specific functional effects, overcoming challenges in studying adaptable proteins.
Area of Science:
- Chemical Biology
- Molecular Cell Biology
- Protein Biochemistry
Background:
- Adaptor proteins regulate multiple protein complexes, complicating their study due to pleiotropic effects upon genetic disruption.
- TRMT112 is a methyltransferase (MT) adaptor involved in various cellular functions through distinct complexoforms.
Purpose of the Study:
- To develop chemical proteomic tools for studying adaptor protein complexoforms.
- To investigate the specific interactions of TRMT112 with methyltransferases (MTs).
Main Methods:
- Chemical proteomic discovery of bicyclopyrrolidine acrylamide stereoprobes.
- Assessing stereoprobe reactivity with recombinant TRMT112 and its complexes with MTs.
- Cocrystallography to determine the binding mode of stereoprobes.
Main Results:
- Stereoprobes selectively reacted with TRMT112 in the presence of METTL5, but not with uncomplexed TRMT112 or other TRMT112:MT complexes.
- Cocrystal structure revealed a composite binding pocket templated by METTL5.
- Stereoprobe binding induced allosteric agonism of METTL5 activity.
Conclusions:
- Covalent ligands can achieve partner-specific functional effects by targeting unique adaptor complexoforms.
- This study provides a novel chemical biology approach to dissect adaptor protein functions in a complexoform-specific manner.
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