8PY2

Cryo-EM structure of the human BRISC dimer complex bound to compound JMS-175-2

This is a non-PDB format compatible entry.

Summary for 8PY2

• Entry DOI: 10.2210/pdb8py2/pdb
• Related: 8PVY
• EMDB information: 17980 18009
• Descriptor: Lys-63-specific deubiquitinase BRCC36, BRISC complex subunit Abraxas 2, BRISC and BRCA1-A complex member 2, ... (6 entities in total)
• Functional Keywords: brisc, brcc36, deubiquitylase, inhibitor, complex, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 16
• Total formula weight: 562632.87

Authors

Chandler, F.,Zeqiraj, E. (deposition date: 2023-07-24, release date: 2025-02-05, Last modification date: 2025-08-20)

Primary citation

Chandler, F.,Reddy, P.A.N.,Bhutda, S.,Ross, R.L.,Datta, A.,Walden, M.,Walker, K.,Di Donato, S.,Cassel, J.A.,Prakesch, M.A.,Aman, A.,Datti, A.,Campbell, L.J.,Foglizzo, M.,Bell, L.,Stein, D.N.,Ault, J.R.,Al-Awar, R.S.,Calabrese, A.N.,Sicheri, F.,Del Galdo, F.,Salvino, J.M.,Greenberg, R.A.,Zeqiraj, E.
Molecular glues that inhibit deubiquitylase activity and inflammatory signaling.
Nat.Struct.Mol.Biol., 2025

PubMed Abstract: 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.

PubMed: 40097626
DOI: 10.1038/s41594-025-01517-5

Experimental method

ELECTRON MICROSCOPY (3.32 Å)