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Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
Published on: January 12, 2024
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Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5.
F Wieland Goetzke1, Steffen M Bernard2, Cheng-Wei Ju3,4
1Department of Chemistry, Scripps Research, La Jolla, CA, USA.
Biorxiv : the Preprint Server for Biology
|June 6, 2025
Summary
Researchers developed chemical probes to study the TRMT112 adaptor protein. These probes specifically target TRMT112 when it interacts with METTL5, revealing partner-specific functions.
Area of Science:
- Biochemistry
- Chemical Biology
- Proteomics
Background:
- Adaptor proteins regulate diverse cellular complexes, making their study challenging due to pleiotropic effects.
- TRMT112 is a methyltransferase (MT) adaptor with multiple complexoforms, complicating functional analysis.
Purpose of the Study:
- To develop chemical proteomic tools to specifically investigate TRMT112 complexoforms.
- To understand how adaptor-MT interactions dictate functional specificity.
Main Methods:
- Chemical proteomic discovery of bicyclopyrrolidine acrylamide stereoprobes.
- In vitro reactivity assays with recombinant TRMT112 and various MTs.
- Co-crystal structure determination of TRMT112 in complex with METTL5 and stereoprobe.
Main Results:
- Stereoprobes selectively react with cysteine-100 (C100) of TRMT112 only when complexed with METTL5.
- Recombinant TRMT112 shows negligible reactivity, which is restored exclusively by METTL5.
- Co-crystal structure reveals a METTL5-templated binding pocket for the stereoprobe near C100.
- Stereoprobe binding induces allosteric agonism of METTL5 activity.
Conclusions:
- Covalent ligands can achieve partner-specific effects by targeting unique adaptor complexoforms.
- METTL5 binding creates a specific pocket on TRMT112 for stereoprobe reactivity.
- This work provides a chemical tool to dissect TRMT112 complexoform-specific functions.
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