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- EMDB-34450: Cryo-EM Structure of the KBTBD2-Cul3-Rbx1 hexameric complex -

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Basic information

Entry
Database: EMDB / ID: EMD-34450
TitleCryo-EM Structure of the KBTBD2-Cul3-Rbx1 hexameric complex
Map data
Sample
  • Complex: KBTBD2-Cul3-Rbx1 hexameric complex
    • Protein or peptide: Cullin-3
    • Protein or peptide: Kelch repeat and BTB domain-containing protein 2
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1
  • Ligand: ZINC ION
Keywordsligase / complex
Function / homology
Function and homology information


positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / liver morphogenesis / POZ domain binding / polar microtubule / nuclear protein quality control by the ubiquitin-proteasome system / COPII vesicle coating / regulation protein catabolic process at postsynapse / anaphase-promoting complex-dependent catabolic process / negative regulation of beige fat cell differentiation ...positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / liver morphogenesis / POZ domain binding / polar microtubule / nuclear protein quality control by the ubiquitin-proteasome system / COPII vesicle coating / regulation protein catabolic process at postsynapse / anaphase-promoting complex-dependent catabolic process / negative regulation of beige fat cell differentiation / RHOBTB3 ATPase cycle / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / embryonic cleavage / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / protein K27-linked ubiquitination / positive regulation of mitotic metaphase/anaphase transition / positive regulation of protein autoubiquitination / RNA polymerase II transcription initiation surveillance / Notch binding / protein neddylation / fibroblast apoptotic process / cell projection organization / NEDD8 ligase activity / negative regulation of Rho protein signal transduction / RHOBTB1 GTPase cycle / negative regulation of response to oxidative stress / VCB complex / Cul5-RING ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / stem cell division / SCF ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / mitotic metaphase chromosome alignment / negative regulation of type I interferon production / Cul2-RING ubiquitin ligase complex / Cul3-RING ubiquitin ligase complex / stress fiber assembly / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / negative regulation of mitophagy / positive regulation of cytokinesis / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Prolactin receptor signaling / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / cullin family protein binding / endoplasmic reticulum to Golgi vesicle-mediated transport / protein monoubiquitination / RHOBTB2 GTPase cycle / sperm flagellum / site of DNA damage / protein autoubiquitination / protein K48-linked ubiquitination / ubiquitin-like ligase-substrate adaptor activity / signal transduction in response to DNA damage / Nuclear events stimulated by ALK signaling in cancer / transcription-coupled nucleotide-excision repair / gastrulation / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / negative regulation of insulin receptor signaling pathway / post-translational protein modification / intrinsic apoptotic signaling pathway / cyclin binding / positive regulation of protein ubiquitination / Regulation of BACH1 activity / T cell activation / integrin-mediated signaling pathway / negative regulation of canonical NF-kappaB signal transduction / lipid metabolic process / kidney development / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Degradation of DVL / Degradation of CRY and PER proteins / G1/S transition of mitotic cell cycle / Degradation of GLI1 by the proteasome / negative regulation of canonical Wnt signaling pathway / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Negative regulation of NOTCH4 signaling / Hedgehog 'on' state / Recognition of DNA damage by PCNA-containing replication complex / Vif-mediated degradation of APOBEC3G / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / RING-type E3 ubiquitin transferase / Degradation of beta-catenin by the destruction complex / response to insulin / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / DNA Damage Recognition in GG-NER / protein destabilization / NOTCH1 Intracellular Domain Regulates Transcription / Evasion by RSV of host interferon responses / Constitutive Signaling by NOTCH1 PEST Domain Mutants
Similarity search - Function
Kelch repeat and BTB domain-containing protein 2 / : / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch / Kelch motif ...Kelch repeat and BTB domain-containing protein 2 / : / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch / Kelch motif / : / Cullin alpha+beta domain / Cullin protein neddylation domain / : / Kelch repeat type 1 / Cullin, conserved site / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin, N-terminal / Cullin alpha solenoid domain / Cullin / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / Kelch-type beta propeller / BTB/POZ domain / BTB domain profile. / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase RBX1 / Cullin-3 / Kelch repeat and BTB domain-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.99 Å
AuthorsHu Y / Mao Q / Chen Z / Sun L
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81900729 China
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Dynamic molecular architecture and substrate recruitment of cullin3-RING E3 ligase CRL3.
Authors: Yuxia Hu / Zhao Zhang / Qiyu Mao / Xiang Zhang / Aihua Hao / Yu Xun / Yeda Wang / Lin Han / Wuqiang Zhan / Qianying Liu / Yue Yin / Chao Peng / Eva Marie Y Moresco / Zhenguo Chen / Bruce Beutler / Lei Sun /
Abstract: Phosphatidylinositol 3-kinase α, a heterodimer of catalytic p110α and one of five regulatory subunits, mediates insulin- and insulin like growth factor-signaling and, frequently, oncogenesis. ...Phosphatidylinositol 3-kinase α, a heterodimer of catalytic p110α and one of five regulatory subunits, mediates insulin- and insulin like growth factor-signaling and, frequently, oncogenesis. Cellular levels of the regulatory p85α subunit are tightly controlled by regulated proteasomal degradation. In adipose tissue and growth plates, failure of K48-linked p85α ubiquitination causes diabetes, lipodystrophy and dwarfism in mice, as in humans with SHORT syndrome. Here we elucidated the structures of the key ubiquitin ligase complexes regulating p85α availability. Specificity is provided by the substrate receptor KBTBD2, which recruits p85α to the cullin3-RING E3 ubiquitin ligase (CRL3). CRL3 forms multimers, which disassemble into dimers upon substrate binding (CRL3-p85α) and/or neddylation by the activator NEDD8 (CRL3~N8), leading to p85α ubiquitination and degradation. Deactivation involves dissociation of NEDD8 mediated by the COP9 signalosome and displacement of KBTBD2 by the inhibitor CAND1. The hereby identified structural basis of p85α regulation opens the way to better understanding disturbances of glucose regulation, growth and cancer.
History
DepositionOct 7, 2022-
Header (metadata) releaseOct 11, 2023-
Map releaseOct 11, 2023-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34450.png

Downloads & links

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Map

FileDownload / File: emd_34450.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
2.66 Å/pix.
x 192 pix.
= 511.488 Å		2.66 Å/pix.
x 192 pix.
= 511.488 Å		2.66 Å/pix.
x 192 pix.
= 511.488 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 2.664 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.001
Minimum - Maximum-0.0013494599 - 1.5533439
Average (Standard dev.)0.0025103877 (±0.033656817)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 511.488 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_34450_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34450_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : KBTBD2-Cul3-Rbx1 hexameric complex

EntireName: KBTBD2-Cul3-Rbx1 hexameric complex
Components
  • Complex: KBTBD2-Cul3-Rbx1 hexameric complex
    • Protein or peptide: Cullin-3
    • Protein or peptide: Kelch repeat and BTB domain-containing protein 2
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1
  • Ligand: ZINC ION

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Supramolecule #1: KBTBD2-Cul3-Rbx1 hexameric complex

SupramoleculeName: KBTBD2-Cul3-Rbx1 hexameric complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cullin-3

MacromoleculeName: Cullin-3 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 89.063328 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSNLSKGTGS RKDTKMRIRA FPMTMDEKYV NSIWDLLKNA IQEIQRKNNS GLSFEELYRN AYTMVLHKHG EKLYTGLREV VTEHLINKV REDVLNSLNN NFLQTLNQAW NDHQTAMVMI RDILMYMDRV YVQQNNVENV YNLGLIIFRD QVVRYGCIRD H LRQTLLDM ...String:
MSNLSKGTGS RKDTKMRIRA FPMTMDEKYV NSIWDLLKNA IQEIQRKNNS GLSFEELYRN AYTMVLHKHG EKLYTGLREV VTEHLINKV REDVLNSLNN NFLQTLNQAW NDHQTAMVMI RDILMYMDRV YVQQNNVENV YNLGLIIFRD QVVRYGCIRD H LRQTLLDM IARERKGEVV DRGAIRNACQ MLMILGLEGR SVYEEDFEAP FLEMSAEFFQ MESQKFLAEN SASVYIKKVE AR INEEIER VMHCLDKSTE EPIVKVVERE LISKHMKTIV EMENSGLVHM LKNGKTEDLG CMYKLFSRVP NGLKTMCECM SSY LREQGK ALVSEEGEGK NPVDYIQGLL DLKSRFDRFL LESFNNDRLF KQTIAGDFEY FLNLNSRSPE YLSLFIDDKL KKGV KGLTE QEVETILDKA MVLFRFMQEK DVFERYYKQH LARRLLTNKS VSDDSEKNMI SKLKTECGCQ FTSKLEGMFR DMSIS NTTM DEFRQHLQAT GVSLGGVDLT VRVLTTGYWP TQSATPKCNI PPAPRHAFEI FRRFYLAKHS GRQLTLQHHM GSADLN ATF YGPVKKEDGS EVGVGGAQVT GSNTRKHILQ VSTFQMTILM LFNNREKYTF EEIQQETDIP ERELVRALQS LACGKPT QR VLTKEPKSKE IENGHIFTVN DQFTSKLHRV KIQTVAAKQG ESDPERKETR QKVDDDRKHE IEAAIVRIMK SRKKMQHN V LVAEVTQQLK ARFLPSPVVI KKRIEGLIER EYLARTPEDR KVYTYVA

UniProtKB: Cullin-3

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Macromolecule #2: Kelch repeat and BTB domain-containing protein 2

MacromoleculeName: Kelch repeat and BTB domain-containing protein 2 / type: protein_or_peptide / ID: 2 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71.403367 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSTQDERQIN TEYAVSLLEQ LKLFYEQQLF TDIVLIVEGT EFPCHKMVLA TCSSYFRAMF MSGLSESKQT HVHLRNVDAA TLQIIITYA YTGNLAMNDS TVEQLYETAC FLQVEDVLQR CREYLIKKIN AENCVRLLSF ADLFSCEELK QSAKRMVEHK F TAVYHQDA ...String:
MSTQDERQIN TEYAVSLLEQ LKLFYEQQLF TDIVLIVEGT EFPCHKMVLA TCSSYFRAMF MSGLSESKQT HVHLRNVDAA TLQIIITYA YTGNLAMNDS TVEQLYETAC FLQVEDVLQR CREYLIKKIN AENCVRLLSF ADLFSCEELK QSAKRMVEHK F TAVYHQDA FMQLSHDLLI DILSSDNLNV EKEETVREAA MLWLEYNTES RSQYLSSVLS QIRIDALSEV TQRAWFQGLP PN DKSVVVQ GLYKSMPKFF KPRLGMTKEE MMIFIEASSE NPCSLYSSVC YSPQAEKVYK LCSPPADLHK VGTVVTPDND IYI AGGQVP LKNTKTNHSK TSKLQTAFRT VNCFYWFDAQ QNTWFPKTPM LFVRIKPSLV CCEGYIYAIG GDSVGGELNR RTVE RYDTE KDEWTMVSPL PCAWQWSAAV VVHDCIYVMT LNLMYCYFPR SDSWVEMAMR QTSRSFASAA AFGDKIFYIG GLHIA TNSG IRLPSGTVDG SSVTVEIYDV NKNEWKMAAN IPAKRYSDPC VRAVVISNSL CVFMRETHLN ERAKYVTYQY DLELDR WSL RQHISERVLW DLGRDFRCTV GKLYPSCLEE SPWKPPTYLF STDGTEEFEL DGEMVALPPV

UniProtKB: Kelch repeat and BTB domain-containing protein 2

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Macromolecule #3: E3 ubiquitin-protein ligase RBX1

MacromoleculeName: E3 ubiquitin-protein ligase RBX1 / type: protein_or_peptide / ID: 3 / Number of copies: 6 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.970756 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
HHHHHHENLY FQGMAAAMDV DTPSGTNSGA GKKRFEVKKW NAVALWAWDI VVDNCAICRN HIMDLCIECQ ANQASATSEE CTVAWGVCN HAFHFHCISR WLKTRQVCPL DNREWEFQKY GH

UniProtKB: E3 ubiquitin-protein ligase RBX1

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 18 / Formula: ZN
Molecular weightTheoretical: 65.409 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

BufferpH: 7.8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6i2m


Details: 4A0K
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 7.99 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 51689
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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