PXD063358

PXD063358 is an original dataset announced via ProteomeXchange.

Title	Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5
Description	Adaptor proteins often serve as hubs to regulate diverse protein complexes in cells. This multitude of functions can complicate the study of adaptors, as their genetic disruption typically impairs the activities of all parent complexes (or ‘complexoforms’). Here we describe the chemical proteomic analysis of bicyclopyrrolidine acrylamide stereoprobes in human cells, leading to the discovery of a ligand – FWG-33B – that stereoselectively reacts with cysteine-100 (C100) of the methyltransferase (MT) adaptor TRMT112. FWG-33B showed negligible reactivity with uncomplexed recombinant TRMT112, and this interaction was restored exclusively in the presence of METTL5, but not other MT partners of TRMT112. A co-crystal structure revealed that FWG-33B binds at a composite pocket proximal to C100 that is templated by METTL5 and absent in other TRMT112:MT complexes. Subtle structural rearrangements promoted by FWG-33B 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.
HostingRepository	PRIDE
AnnounceDate	2026-01-08
AnnouncementXML	Submission_2026-01-08_06:19:30.890.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Friedrich Wieland Goetzke
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-26 17:10:07	ID requested
⏵ 1	2026-01-08 06:19:31	announced

10.1038/S41589-025-02099-5;

submitter keyword: None

Benjamin Cravatt
contact affiliation	Scripps Research, US
contact email	cravatt@scripps.edu
lab head
Friedrich Wieland Goetzke
contact affiliation	Scripps Research
contact email	fgoetzke@scripps.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/01/PXD063358

PRIDE project URI

• PRIDE
  1. PXD063358
     1. Label: PRIDE project
     2. Name: Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5