PXD044584

PXD044584 is an original dataset announced via ProteomeXchange.

Title	First-in-class DUB Molecular Glues and Inhibitors of Inflammation
Description	Deubiquitylases (DUBs) play a pivotal role in cell signalling and are often regulated by homo- or hetero-interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by selectively cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1/2). BRCC36 is a Zn2+-dependent JAMM/MPN DUB and a challenging target for selective inhibitors. We identified first-in-class DUB inhibitors that act as BRISC molecular glues (BLUEs). BLUEs inhibit DUB activity by stabilising a BRISC dimer consisting of 16 subunits. The BRISC dimer is an autoinhibited conformation, whereby the active sites and binding sites for the recruiting subunit SHMT2 are blocked. This unique mode of action leads to highly selective compounds for BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. Structure-guided inhibitor-insensitive BRISC mutants confirm BLUEs on-target activity in cells by lowering immune signalling intensity and duration, and by accelerating IFNAR1 degradation. We demonstrate a route to develop selective inhibitors through stabilising interactions with molecular glues and identify a new class of molecules for lowering inflammation in interferon-mediated conditions and autoimmune disease.
HostingRepository	PRIDE
AnnounceDate	2025-02-06
AnnouncementXML	Submission_2025-02-06_05:36:49.586.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Francesca Chandler
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-15 01:54:12	ID requested
⏵ 1	2025-02-06 05:36:50	announced

10.1101/2024.09.07.611787;

Chandler F, Reddy PAN, Bhutda S, Ross RL, Datta A, Walden M, Walker K, Di Donato S, Cassel JA, Prakesch MA, Aman A, Datti A, Campbell LJ, Foglizzo M, Bell L, Stein DN, Ault JR, Al-Awar RS, Calabrese AN, Sicheri F, Del Galdo F, Salvino JM, Greenberg RA, Zeqiraj E, Molecular glues that inhibit deubiquitylase activity and inflammatory signalling. bioRxiv, ():(2024) [pubmed]

submitter keyword: inhibitor,molecular glues, hydrogen deuterium exchange, hdx, deubiquitylase

Elton Zeqiraj
contact affiliation	Astbury Centre for Structural Molecular Biology and School of Molecular and Cellulat Biology, University of Leeds
contact email	e.zeqiraj@leeds.ac.uk
lab head
Francesca Chandler
contact affiliation	University of Leeds
contact email	fbsfcha@leeds.ac.uk
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/2025/02/PXD044584

PRIDE project URI

• PRIDE
  1. PXD044584
     1. Label: PRIDE project
     2. Name: First-in-class DUB Molecular Glues and Inhibitors of Inflammation