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- EMDB-17980: Cryo-EM structure of the human BRISC dimer complex bound to compo... -

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Entry
Database: EMDB / ID: EMD-17980
TitleCryo-EM structure of the human BRISC dimer complex bound to compound FX-171-C
Map data
Sample
  • Complex: BRISC dimer in complex with inhibitor FX-171-C
    • Protein or peptide: Lys-63-specific deubiquitinase BRCC36
    • Protein or peptide: BRISC complex subunit Abraxas 2
    • Protein or peptide: BRISC and BRCA1-A complex member 2
    • Protein or peptide: BRISC and BRCA1-A complex member 1
  • Ligand: ZINC ION
  • Ligand: N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]-1-[2,6-bis(chloranyl)phenyl]carbonyl-4-[[2,6-bis(chloranyl)phenyl]carbonylamino]pyrazole-3-carboxamide
KeywordsBRISC / BRCC36 / deubiquitylase / inhibitor / complex / SIGNALING PROTEIN
Function / homology
Function and homology information


peroxisome targeting sequence binding / BRISC complex / BRCA1-A complex / attachment of spindle microtubules to kinetochore / nuclear ubiquitin ligase complex / Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases / regulation of DNA damage checkpoint / mitotic G2/M transition checkpoint / tumor necrosis factor receptor binding / metal-dependent deubiquitinase activity ...peroxisome targeting sequence binding / BRISC complex / BRCA1-A complex / attachment of spindle microtubules to kinetochore / nuclear ubiquitin ligase complex / Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases / regulation of DNA damage checkpoint / mitotic G2/M transition checkpoint / tumor necrosis factor receptor binding / metal-dependent deubiquitinase activity / protein K63-linked deubiquitination / K63-linked deubiquitinase activity / response to ionizing radiation / hematopoietic stem cell proliferation / DNA repair-dependent chromatin remodeling / positive regulation of NLRP3 inflammasome complex assembly / mitotic G2 DNA damage checkpoint signaling / polyubiquitin modification-dependent protein binding / protein deubiquitination / mitotic spindle assembly / response to X-ray / ubiquitin ligase complex / regulation of DNA repair / enzyme regulator activity / cellular response to ionizing radiation / positive regulation of DNA repair / response to ischemia / chromosome segregation / Nonhomologous End-Joining (NHEJ) / G2/M DNA damage checkpoint / Metalloprotease DUBs / spindle pole / metallopeptidase activity / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / double-strand break repair / mitotic cell cycle / Processing of DNA double-strand break ends / chromatin organization / microtubule binding / microtubule / cysteine-type deubiquitinase activity / nuclear body / ciliary basal body / cell division / apoptotic process / DNA damage response / negative regulation of apoptotic process / signal transduction / proteolysis / nucleoplasm / metal ion binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
BRISC and BRCA1-A complex member 1 / FAM175 family, BRISC complex, Abro1 subunit / BRCA1-A complex subunit BRE / Brain and reproductive organ-expressed protein (BRE) / Brcc36 isopeptidase / BRCC36, C-terminal helical domain / BRCC36 C-terminal helical domain / FAM175 family / BRCA1-A complex subunit Abraxas 1 MPN domain / : ...BRISC and BRCA1-A complex member 1 / FAM175 family, BRISC complex, Abro1 subunit / BRCA1-A complex subunit BRE / Brain and reproductive organ-expressed protein (BRE) / Brcc36 isopeptidase / BRCC36, C-terminal helical domain / BRCC36 C-terminal helical domain / FAM175 family / BRCA1-A complex subunit Abraxas 1 MPN domain / : / JAB1/Mov34/MPN/PAD-1 ubiquitin protease / JAB/MPN domain / JAB1/MPN/MOV34 metalloenzyme domain / MPN domain / MPN domain profile. / von Willebrand factor A-like domain superfamily
Similarity search - Domain/homology
Lys-63-specific deubiquitinase BRCC36 / BRISC complex subunit Abraxas 2 / BRISC and BRCA1-A complex member 1 / BRISC and BRCA1-A complex member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.02 Å
AuthorsChandler F / Zeqiraj E
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Wellcome Trust219997/Z/19/Z United Kingdom
Wellcome Trust United Kingdom
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Molecular glues that inhibit deubiquitylase activity and inflammatory signaling.
Authors: Francesca 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 ...Authors: Francesca 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 /
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 ...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.
History
DepositionJul 18, 2023-
Header (metadata) releaseFeb 12, 2025-
Map releaseFeb 12, 2025-
UpdateAug 20, 2025-
Current statusAug 20, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17980.png

Downloads & links

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Map

FileDownload / File: emd_17980.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.71 Å/pix.
x 384 pix.
= 272.602 Å		0.71 Å/pix.
x 384 pix.
= 272.602 Å		0.71 Å/pix.
x 384 pix.
= 272.602 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.7099 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.008103291 - 0.026601149
Average (Standard dev.)0.00009942247 (±0.0011074406)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 272.60162 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_17980_msk_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #2

Fileemd_17980_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_17980_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : BRISC dimer in complex with inhibitor FX-171-C

EntireName: BRISC dimer in complex with inhibitor FX-171-C
Components
  • Complex: BRISC dimer in complex with inhibitor FX-171-C
    • Protein or peptide: Lys-63-specific deubiquitinase BRCC36
    • Protein or peptide: BRISC complex subunit Abraxas 2
    • Protein or peptide: BRISC and BRCA1-A complex member 2
    • Protein or peptide: BRISC and BRCA1-A complex member 1
  • Ligand: ZINC ION
  • Ligand: N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]-1-[2,6-bis(chloranyl)phenyl]carbonyl-4-[[2,6-bis(chloranyl)phenyl]carbonylamino]pyrazole-3-carboxamide

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Supramolecule #1: BRISC dimer in complex with inhibitor FX-171-C

SupramoleculeName: BRISC dimer in complex with inhibitor FX-171-C / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 654 KDa

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Macromolecule #1: Lys-63-specific deubiquitinase BRCC36

MacromoleculeName: Lys-63-specific deubiquitinase BRCC36 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.703492 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAVQVVQAVQ AVHLESDAFL VCLNHALSTE KEEVMGLCIG ELNDDTRSDS KFAYTGTEMR TVAEKVDAVR IVHIHSVIIL RRSDKRKDR VEISPEQLSA ASTEAERLAE LTGRPMRVVG WYHSHPHITV WPSHVDVRTQ AMYQMMDQGF VGLIFSCFIE D KNTKTGRV ...String:
MAVQVVQAVQ AVHLESDAFL VCLNHALSTE KEEVMGLCIG ELNDDTRSDS KFAYTGTEMR TVAEKVDAVR IVHIHSVIIL RRSDKRKDR VEISPEQLSA ASTEAERLAE LTGRPMRVVG WYHSHPHITV WPSHVDVRTQ AMYQMMDQGF VGLIFSCFIE D KNTKTGRV LYTCFQSIQA QKSSESLHGP RDFWSSSQHI SIEGQKEEER YERIEIPIHI VPHVTIGKVC LESAVELPKI LC QEEQDAY RRIHSLTHLD SVTKIHNGSV FTKNLCSQMS AVSGPLLQWL EDRLEQNQQH LQELQQEKEE LMQEL

UniProtKB: Lys-63-specific deubiquitinase BRCC36

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Macromolecule #2: BRISC complex subunit Abraxas 2

MacromoleculeName: BRISC complex subunit Abraxas 2 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 31.033945 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAASISGYTF SAVCFHSANS NADHEGFLLG EVRQEETFSI SDSQISNTEF LQVIEIHNHQ PCSKLFSFYD YASKVNEESL DRILKDRRK KVIGWYRFRR NTQQQMSYRE QVLHKQLTRI LGVPDLVFLL FSFISTANNS THALEYVLFR PNRRYNQRIS L AIPNLGNT ...String:
MAASISGYTF SAVCFHSANS NADHEGFLLG EVRQEETFSI SDSQISNTEF LQVIEIHNHQ PCSKLFSFYD YASKVNEESL DRILKDRRK KVIGWYRFRR NTQQQMSYRE QVLHKQLTRI LGVPDLVFLL FSFISTANNS THALEYVLFR PNRRYNQRIS L AIPNLGNT SQQEYKVSSV PNTSQSYAKV IKEHGTDFFD KDGVMKDIRA IYQVYNALQE KVQAVCADVE KSERVVESCQ AE VNKLRRQ ITQRKNEKEQ ERRLQQAVLS

UniProtKB: BRISC complex subunit Abraxas 2

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Macromolecule #3: BRISC and BRCA1-A complex member 2

MacromoleculeName: BRISC and BRCA1-A complex member 2 / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.721602 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GAMSPEVALN RISPMLSPFI SSVVRNGKVG LDATNCLRIT DLKSGCTSLT PGPNCDRFKL HIPYAGETLK WDIIFNAQYP ELPPDFIFG EDAEFLPDPS ALQNLASWNP SNPECLLLVV KELVQQYHQF QCSRLRESSR LMFEYQTLLE EPQYGENMEI Y AGKKNNWT ...String:
GAMSPEVALN RISPMLSPFI SSVVRNGKVG LDATNCLRIT DLKSGCTSLT PGPNCDRFKL HIPYAGETLK WDIIFNAQYP ELPPDFIFG EDAEFLPDPS ALQNLASWNP SNPECLLLVV KELVQQYHQF QCSRLRESSR LMFEYQTLLE EPQYGENMEI Y AGKKNNWT GEFSARFLLK LPVDFSNIPT YLLKDVNEDP GEDVALLSVS FEDTEATQVY PKLYLSPRIE HALGGSSALH IP AFPGGGC LIDYVPQVCH LLTNKVQYVI QGYHKRREYI AAFLSHFGTG VVEYDAEGFT KLTLLLMWKD FCFLVHIDLP LFF PRDQPT LTFQSVYHFT NSGQLYSQAQ KNYPYSPRWD GNEMAKRAKA YFKTFVPQFQ EAAFANGKL

UniProtKB: BRISC and BRCA1-A complex member 2

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Macromolecule #4: BRISC and BRCA1-A complex member 1

MacromoleculeName: BRISC and BRCA1-A complex member 1 / type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.439723 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSWQVPPPAP EVQIRTPRVN CPEKVIICLD LSEEMSLPKL ESFNGSKTNA LNVSQKMIEM FVRTKHKIDK SHEFALVVVN DDTAWLSGL TSDPRELCSC LYDLETASCS TFNLEGLFSL IQQKTELPVT ENVQTIPPPY VVRTILVYSR PPCQPQFSLT E PMKKMFQC ...String:
MSWQVPPPAP EVQIRTPRVN CPEKVIICLD LSEEMSLPKL ESFNGSKTNA LNVSQKMIEM FVRTKHKIDK SHEFALVVVN DDTAWLSGL TSDPRELCSC LYDLETASCS TFNLEGLFSL IQQKTELPVT ENVQTIPPPY VVRTILVYSR PPCQPQFSLT E PMKKMFQC PYFFFDVVYI HNGTEEKEEE MSWKDMFAFM GSLDTKGTSY KYEVALAGPA LELHNCMAKL LAHPLQRPCQ SH ASYSLLE EEDEAIEVEA TV

UniProtKB: BRISC and BRCA1-A complex member 1

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #6: N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]-1-[2,6-bis(chloranyl)ph...

MacromoleculeName: N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]-1-[2,6-bis(chloranyl)phenyl]carbonyl-4-[[2,6-bis(chloranyl)phenyl]carbonylamino]pyrazole-3-carboxamide
type: ligand / ID: 6 / Number of copies: 2 / Formula: G1V
Molecular weightTheoretical: 553.225 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.3 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
150.0 mMNaClsodium chloride
1.0 mMTCEPtris(2-carboxyethyl)phosphine

Details: 25 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TCEP
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsBRISCdNdC at 0.7 mg/mL (5 uM) was mixed with FX-171-C at 400 uM.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 16750 / Average exposure time: 3.43 sec. / Average electron dose: 34.97 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.6 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2458785
CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Details: Map generated in RELION from a previous data collection of a similar sample, low-pass filtered and used as an initial model for 3D classification.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.1) / Number images used: 632988
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.1)
Final 3D classificationSoftware - Name: RELION (ver. 3.1.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8pvy:
Cryo-EM structure of the human BRISC dimer complex bound to compound FX-171-C

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