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- PDB-8pvy: Cryo-EM structure of the human BRISC dimer complex bound to compo... -

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Basic information

Entry
Database: PDB / ID: 8pvy
TitleCryo-EM structure of the human BRISC dimer complex bound to compound FX-171-C
Components
  • (BRISC and BRCA1-A complex member ...) x 2
  • BRISC complex subunit Abraxas 2
  • Lys-63-specific deubiquitinase BRCC36
KeywordsSIGNALING PROTEIN / BRISC / BRCC36 / deubiquitylase / inhibitor / complex
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.02 Å
AuthorsChandler, F. / Zeqiraj, E.
Funding support United Kingdom, 2items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.1Aug 20, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lys-63-specific deubiquitinase BRCC36
B: BRISC complex subunit Abraxas 2
C: Lys-63-specific deubiquitinase BRCC36
D: BRISC complex subunit Abraxas 2
E: BRISC and BRCA1-A complex member 2
F: BRISC and BRCA1-A complex member 2
G: Lys-63-specific deubiquitinase BRCC36
H: BRISC complex subunit Abraxas 2
I: Lys-63-specific deubiquitinase BRCC36
J: BRISC complex subunit Abraxas 2
K: BRISC and BRCA1-A complex member 2
L: BRISC and BRCA1-A complex member 2
M: BRISC and BRCA1-A complex member 1
N: BRISC and BRCA1-A complex member 1
O: BRISC and BRCA1-A complex member 1
P: BRISC and BRCA1-A complex member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)560,96322
Polymers559,59516
Non-polymers1,3686
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable, mass spectrometry, native mass spectrometry indicated a 654 kDa complex, assay for oligomerization, mass photometry identified a 652 kDa complex
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 8 molecules ACGIBDHJ

#1: Protein
Lys-63-specific deubiquitinase BRCC36 / BRCA1-A complex subunit BRCC36 / BRCA1/BRCA2-containing complex subunit 3 / BRCA1/BRCA2-containing ...BRCA1-A complex subunit BRCC36 / BRCA1/BRCA2-containing complex subunit 3 / BRCA1/BRCA2-containing complex subunit 36 / BRISC complex subunit BRCC36


Mass: 35703.492 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRCC3, BRCC36, C6.1A, CXorf53 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P46736, Hydrolases; Acting on peptide bonds (peptidases); Omega peptidases
#2: Protein
BRISC complex subunit Abraxas 2 / Abraxas brother protein 1 / Protein FAM175B


Mass: 31033.945 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABRAXAS2, ABRO1, FAM175B, KIAA0157 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q15018

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BRISC and BRCA1-A complex member ... , 2 types, 8 molecules EFKLMNOP

#3: Protein
BRISC and BRCA1-A complex member 2 / BRCA1-A complex subunit BRE / BRCA1/BRCA2-containing complex subunit 45 / Brain and reproductive ...BRCA1-A complex subunit BRE / BRCA1/BRCA2-containing complex subunit 45 / Brain and reproductive organ-expressed protein


Mass: 43721.602 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BABAM2, BRCC45, BRE / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9NXR7
#4: Protein
BRISC and BRCA1-A complex member 1 / Mediator of RAP80 interactions and targeting subunit of 40 kDa / New component of the BRCA1-A complex


Mass: 29439.723 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BABAM1, C19orf62, MERIT40, NBA1, HSPC142 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9NWV8

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Non-polymers , 2 types, 6 molecules

#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-G1V / 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 / N-(3-azabicyclo[3.1.0]hexan-6-yl)-4-(2,6-dichlorobenzamido)-1-(2,6-dichlorobenzoyl)-1H-pyrazole-3-carboxamide


Mass: 553.225 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H17Cl4N5O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: BRISC dimer in complex with inhibitor FX-171-C / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.654 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5 / Details: 25 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TCEP
Buffer component
IDConc.NameFormulaBuffer-ID
125 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
2150 mMsodium chlorideNaCl1
31 mMtris(2-carboxyethyl)phosphineTCEP1
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: BRISCdNdC at 0.7 mg/mL (5 uM) was mixed with FX-171-C at 400 uM.
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1600 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.43 sec. / Electron dose: 34.97 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 16750
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1crYOLO1.6.1particle selection
2EPU3.2.0image acquisition
4CTFFINDCTF correction
9RELION3.1.1initial Euler assignment
10RELION3.1.1final Euler assignment
11RELION3.1.1classification
12RELION3.1.13D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2458785
3D reconstructionResolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 632988 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL

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