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

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Basic information

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 / DNA repair-dependent chromatin remodeling / hematopoietic stem cell proliferation / 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 / positive regulation of DNA repair / response to ischemia / cellular response to ionizing radiation / chromosome segregation / Nonhomologous End-Joining (NHEJ) / G2/M DNA damage checkpoint / Metalloprotease DUBs / spindle pole / metallopeptidase activity / double-strand break repair / mitotic cell cycle / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromatin organization / Processing of DNA double-strand break ends / microtubule binding / microtubule / cysteine-type deubiquitinase activity / nuclear body / cell division / apoptotic process / DNA damage response / negative regulation of apoptotic process / signal transduction / proteolysis / nucleoplasm / identical protein binding / nucleus / metal ion binding / 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: To be published
Title: First-in-class DUB Molecular Glues and Inhibitors of Inflammation
Authors: Chandler F / Reddy P / Bhutda S / Ross R / Walden M / Walker K / Cassel J / Prakesch M / Datti A / Campbell L / Foglizzo M / Bell L / Ault J / Al-awar R / Calabrese A / Sicheri F / Del Galdo ...Authors: Chandler F / Reddy P / Bhutda S / Ross R / Walden M / Walker K / Cassel J / Prakesch M / Datti A / Campbell L / Foglizzo M / Bell L / Ault J / Al-awar R / Calabrese A / Sicheri F / Del Galdo F / Salvino J / Greenberg R / Zeqiraj E
History
DepositionJul 18, 2023-
Header (metadata) releaseFeb 12, 2025-
Map releaseFeb 12, 2025-
UpdateFeb 12, 2025-
Current statusFeb 12, 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)

Slices (1/2)

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
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_17980_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_17980_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

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
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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