9OHL

TRMT112-METTL5 bound to SAM and FWG-33B

This is a non-PDB format compatible entry.

Summary for 9OHL

• Entry DOI: 10.2210/pdb9ohl/pdb
• Descriptor: rRNA N(6)-adenosine-methyltransferase METTL5, Multifunctional methyltransferase subunit TRM112-like protein, S-ADENOSYLMETHIONINE, ... (6 entities in total)
• Functional Keywords: trna methyltransferase 112 homolog, methyltransferase-like protein 5, stereoselective probe, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 38885.37

Authors

Goetzke, F.W.,Bernard, S.M. (deposition date: 2025-05-05, release date: 2025-06-11, Last modification date: 2025-06-18)

Primary citation

Goetzke, F.W.,Bernard, S.M.,Ju, C.W.,Pollock, J.,DeMeester, K.E.,Gross, J.,Simon, G.M.,He, C.,Melillo, B.,Cravatt, B.F.
Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5.
Biorxiv, 2025

PubMed 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 cysteine-100 (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 excluively in the presence of METTL5, but not other MTs. A co-crystal 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.

PubMed: 40475643
DOI: 10.1101/2025.05.25.655995

Experimental method

X-RAY DIFFRACTION (1.286 Å)