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TitleMolecular glues that inhibit deubiquitylase activity and inflammatory signaling.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 9, Page 1812-1824, Year 2025
Publish dateMar 17, 2025
AuthorsFrancesca Chandler / Poli Adi Narayana Reddy / Smita Bhutda / Rebecca L Ross / Arindam Datta / Miriam Walden / Kieran Walker / Stefano Di Donato / Joel A Cassel / Michael A Prakesch / Ahmed Aman / Alessandro Datti / Lisa J Campbell / Martina Foglizzo / Lillie Bell / Daniel N Stein / James R Ault / Rima S Al-Awar / Antonio N Calabrese / Frank Sicheri / Francesco Del Galdo / Joseph M Salvino / Roger A Greenberg / Elton Zeqiraj /
PubMed AbstractDeubiquitylases (DUBs) are crucial in cell signaling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signaling by ...Deubiquitylases (DUBs) are crucial in cell signaling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signaling by cleaving K63-linked polyubiquitin chains on type I interferon receptors (IFNAR1). As a Zn-dependent JAMM/MPN (JAB1, MOV34, MPR1, Pad1 N-terminal) DUB, BRCC36 is challenging to target with selective inhibitors. Here, we discover first-in-class inhibitors, termed BRISC molecular glues (BLUEs), which stabilize a 16-subunit human BRISC dimer in an autoinhibited conformation, blocking active sites and interactions with the targeting subunit, serine hydroxymethyltransferase 2. This unique mode of action results in selective inhibition of BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. BLUE treatment reduced interferon-stimulated gene expression in cells containing wild-type BRISC and this effect was abolished when using structure-guided, inhibitor-resistant BRISC mutants. Additionally, BLUEs increase IFNAR1 ubiquitylation and decrease IFNAR1 surface levels, offering a potential strategy to mitigate type I interferon-mediated diseases. Our approach also provides a template for designing selective inhibitors of large protein complexes by promoting rather than blocking protein-protein interactions.
External linksNat Struct Mol Biol / PubMed:40097626 / PubMed Central
MethodsEM (single particle)
Resolution3.02 - 3.32 Å
Structure data

17980

8pvy

EMDB-17980, PDB-8pvy:
Cryo-EM structure of the human BRISC dimer complex bound to compound FX-171-C
Method: EM (single particle) / Resolution: 3.02 Å

18009

8py2

EMDB-18009, PDB-8py2:
Cryo-EM structure of the human BRISC dimer complex bound to compound JMS-175-2
Method: EM (single particle) / Resolution: 3.32 Å

Chemicals

ChemComp-ZN:
Unknown entry


ChemComp, No image

ChemComp-G1V:
Unknown entry


ChemComp, No image

ChemComp-X8C:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / BRISC / BRCC36 / deubiquitylase / inhibitor / complex

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