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- PDB-8py2: Cryo-EM structure of the human BRISC dimer complex bound to compo... -

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Basic information

Entry
Database: PDB / ID: 8py2
TitleCryo-EM structure of the human BRISC dimer complex bound to compound JMS-175-2
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 / 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 / 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: 3.32 Å
AuthorsChandler, F. / Zeqiraj, E.
Funding support United Kingdom, 2items
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. / Campbell, L. / Foglizzo, M. / Bell, L. / Ault, J. / Al-awar, R. / Calabrese, A. / ...Authors: Chandler, F. / Reddy, P. / Bhutda, S. / Ross, R. / Walden, M. / Walker, K. / Cassel, J. / Prakesch, M. / 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 24, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 5, 2025Provider: repository / Type: Initial release

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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)562,63322
Polymers561,26116
Non-polymers1,3726
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: 36119.918 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-X8C / 1-[2,6-bis(chloranyl)phenyl]carbonyl-4-[[2,6-bis(chloranyl)phenyl]carbonylamino]-N-piperidin-4-yl-pyrazole-3-carboxamide / 4-(2,6-dichlorobenzamido)-1-(2,6-dichlorobenzoyl)-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide


Mass: 555.241 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H19Cl4N5O3 / 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 JMS-175-2 / 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 0.3 mg/mL (2 uM) was mixed with JMS-175-2 at 200 uM.
Specimen supportDetails: 30 seconds, 40 mA / Grid 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: 96000 X / Nominal defocus max: 3100 nm / Nominal defocus min: 1700 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 5.99 sec. / Electron dose: 39.84 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 7768

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Processing

EM software
IDNameVersionCategory
2EPU3.2.0image acquisition
4GctfCTF correction
10RELION3.1.1initial Euler assignment
11RELION3.1.1final Euler assignment
12RELION3.1.1classification
13RELION3.1.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 371872 / Symmetry type: POINT

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