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- PDB-9t7v: Structure of LRRC58-EloB/C-CDO1 in complex with NEDD8-CUL5-RBX2-A... -

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Basic information

Entry
Database: PDB / ID: 9t7v
TitleStructure of LRRC58-EloB/C-CDO1 in complex with NEDD8-CUL5-RBX2-ARIH2-Ub
Components
  • Cullin-5
  • Cysteine dioxygenase type 1
  • E3 ubiquitin-protein ligase ARIH2
  • Elongin-B
  • Elongin-C
  • Leucine-rich repeat-containing protein 58
  • NEDD8
  • RING-box protein 2
  • Ubiquitin
KeywordsLIGASE / Cullin / E3 ligase / Ubiquitin
Function / homology
Function and homology information


sulfur amino acid biosynthetic process / negative regulation of focal adhesion disassembly / developmental cell growth / Degradation of cysteine and homocysteine / taurine biosynthetic process / cysteine dioxygenase / cysteine dioxygenase activity / response to azide / RBR-type E3 ubiquitin transferase / L-cysteine catabolic process ...sulfur amino acid biosynthetic process / negative regulation of focal adhesion disassembly / developmental cell growth / Degradation of cysteine and homocysteine / taurine biosynthetic process / cysteine dioxygenase / cysteine dioxygenase activity / response to azide / RBR-type E3 ubiquitin transferase / L-cysteine catabolic process / ERBB2 signaling pathway / : / negative regulation of focal adhesion assembly / reelin-mediated signaling pathway / cellular response to camptothecin / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / regulation of neuron migration / target-directed miRNA degradation / elongin complex / protein K11-linked ubiquitination / protein neddylation / response to glucagon / ubiquitin conjugating enzyme binding / NEDD8 ligase activity / response to redox state / : / VCB complex / Cul5-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / hematopoietic stem cell proliferation / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin ligase complex scaffold activity / nickel cation binding / TGF-beta receptor signaling activates SMADs / regulation of proteolysis / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / response to amino acid / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / regulation of postsynapse assembly / cullin family protein binding / anatomical structure morphogenesis / response to cAMP / ubiquitin ligase complex / protein K63-linked ubiquitination / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / site of DNA damage / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / lactation / endoplasmic reticulum unfolded protein response / protein K48-linked ubiquitination / RNA Polymerase II Pre-transcription Events / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / IRAK2 mediated activation of TAK1 complex / Prevention of phagosomal-lysosomal fusion / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Endosomal Sorting Complex Required For Transport (ESCRT) / Membrane binding and targetting of GAG proteins / Negative regulation of FLT3 / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / post-translational protein modification / Constitutive Signaling by NOTCH1 HD Domain Mutants / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / intrinsic apoptotic signaling pathway / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / APC-Cdc20 mediated degradation of Nek2A / p75NTR recruits signalling complexes / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / NF-kB is activated and signals survival / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Regulation of pyruvate metabolism / response to glucocorticoid / Pexophagy / Regulation of innate immune responses to cytosolic DNA / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Regulation of PTEN localization / VLDLR internalisation and degradation
Similarity search - Function
: / : / : / E3 ubiquitin-protein ligase ARIH2, N-terminal UBA domain / Ariadne domain / Ariadne domain / E3 ubiquitin ligase RBR family / IBR domain, a half RING-finger domain / Nedd8-like ubiquitin / IBR domain ...: / : / : / E3 ubiquitin-protein ligase ARIH2, N-terminal UBA domain / Ariadne domain / Ariadne domain / E3 ubiquitin ligase RBR family / IBR domain, a half RING-finger domain / Nedd8-like ubiquitin / IBR domain / Cysteine dioxygenase type I / Cysteine dioxygenase type I / IBR domain / In Between Ring fingers / TRIAD supradomain / TRIAD supradomain profile. / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Cullin, N-terminal / Cullin protein neddylation domain / : / Cullin, conserved site / Cullin alpha solenoid domain / Cullin family signature. / Elongin-C / Elongin B / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin / : / Cullin alpha+beta domain / Leucine Rich Repeat / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / RmlC-like cupin domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Leucine-rich repeat profile. / SKP1/BTB/POZ domain superfamily / Ring finger / RmlC-like jelly roll fold / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
: / 5-azanylpentan-2-one / E3 ubiquitin-protein ligase ARIH2 / Polyubiquitin-C / Elongin-C / Elongin-B / Ubiquitin-like protein NEDD8 / Cysteine dioxygenase type 1 / Cullin-5 / Leucine-rich repeat-containing protein 58 / RING-box protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsStier, L. / Andree, G.A. / Schulman, B.A.
Funding supportEuropean Union, Germany, 2items
OrganizationGrant numberCountry
European Research Council (ERC)101098161European Union
Boehringer Ingelheim Fonds (BIF) Germany
CitationJournal: Nat Commun / Year: 2026
Title: Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1.
Authors: Gisele A Andree / Luca J Stier / Kerstin Schmiederer / Alina S Thielen / Luis Schmid / Samuel A Maiwald / Karthik V Gottemukkala / Jiale Du / Susanne von Gronau / Claudia Strasser / Judith ...Authors: Gisele A Andree / Luca J Stier / Kerstin Schmiederer / Alina S Thielen / Luis Schmid / Samuel A Maiwald / Karthik V Gottemukkala / Jiale Du / Susanne von Gronau / Claudia Strasser / Judith Müller / Lukas T Henneberg / Camille Guyot / Gary Kleiger / Matthias Mann / Peter J Murray / Brenda A Schulman /
Abstract: Cellular responses to amino acid fluctuations often hinge on ubiquitin-mediated control of metabolic enzymes, yet the underlying E3 ligase pathways remain poorly defined. Using quantitative ...Cellular responses to amino acid fluctuations often hinge on ubiquitin-mediated control of metabolic enzymes, yet the underlying E3 ligase pathways remain poorly defined. Using quantitative proteomics and active cullin-RING ligase (CRL) profiling, we identify LRRC58 as a cysteine-responsive substrate receptor whose stability increases sharply under cysteine starvation. Proteomics reveals an inverse relationship between LRRC58 and the metabolic enzyme cysteine dioxygenase 1 (CDO1), suggesting a cysteine-linked regulatory axis. Biochemical reconstitution and cryo-EM structures show that LRRC58 forms an active CUL2- or CUL5-based CRL that selectively positions CDO1 for ubiquitylation at Lys8. Disease mutant versions of CDO1 mapping to the LRRC58 interface and impaired for the endogenous ubiquitylation pathway were degraded through orthogonal targeting by a VHL-based degrader. Together, our proteomics-guided discovery pipeline, cellular stability studies, and structural analyses uncover a metabolically-tuned LRRC58-CDO1 pathway that links cysteine availability to selective proteasomal turnover, reveals principles of metabolite-regulated CRL activity, and showcases mechanisms distinguishing endogenous and targeted protein degradation.
History
DepositionNov 12, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 20, 2026Provider: repository / Type: Initial release
Revision 1.0May 20, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 20, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0May 20, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 20, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cysteine dioxygenase type 1
R: RING-box protein 2
U: Ubiquitin
O: Elongin-C
N: NEDD8
C: Cullin-5
H: E3 ubiquitin-protein ligase ARIH2
I: Elongin-B
B: Leucine-rich repeat-containing protein 58
hetero molecules


Theoretical massNumber of molelcules
Total (without water)268,00319
Polymers267,3239
Non-polymers68010
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 9 types, 9 molecules ARUONCHIB

#1: Protein Cysteine dioxygenase type 1 / Cysteine dioxygenase type I / CDO / CDO-I


Mass: 22867.576 Da / Num. of mol.: 1 / Mutation: K8C, C76A, C93S, C130A, C164S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDO1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q16878, cysteine dioxygenase
#2: Protein RING-box protein 2 / Rbx2 / CKII beta-binding protein 1 / CKBBP1 / RING finger protein 7 / Regulator of cullins 2 / ...Rbx2 / CKII beta-binding protein 1 / CKBBP1 / RING finger protein 7 / Regulator of cullins 2 / Sensitive to apoptosis gene protein


Mass: 12280.944 Da / Num. of mol.: 1 / Mutation: N-terminal residues 1-4 deleted
Source method: isolated from a genetically manipulated source
Details: N-terminal residues 1-4 deleted / Source: (gene. exp.) Homo sapiens (human) / Gene: RNF7, RBX2, ROC2, SAG / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9UBF6, RING-type E3 ubiquitin transferase, cullin-RING-type E3 NEDD8 transferase
#3: Protein Ubiquitin


Mass: 8519.778 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: contains Ubiquitin residues 1-75 / Source: (gene. exp.) Homo sapiens (human) / Gene: UBC / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG48
#4: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 12485.135 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q15369
#5: Protein NEDD8 / Neddylin / Neural precursor cell expressed developmentally down-regulated protein 8 / NEDD-8 / ...Neddylin / Neural precursor cell expressed developmentally down-regulated protein 8 / NEDD-8 / Ubiquitin-like protein Nedd8


Mass: 8573.978 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NEDD8 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15843
#6: Protein Cullin-5 / CUL-5 / Vasopressin-activated calcium-mobilizing receptor 1 / VACM-1


Mass: 91085.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL5, VACM1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q93034
#7: Protein E3 ubiquitin-protein ligase ARIH2 / ARI-2 / Protein ariadne-2 homolog / Triad1 protein


Mass: 57735.695 Da / Num. of mol.: 1 / Mutation: L381A,E382A,E455A,
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARIH2, ARI2, TRIAD1, HT005 / Production host: Escherichia coli (E. coli)
References: UniProt: O95376, RBR-type E3 ubiquitin transferase
#8: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 13147.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#9: Protein Leucine-rich repeat-containing protein 58


Mass: 40626.605 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRRC58 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96CX6

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Non-polymers , 3 types, 10 molecules

#10: Chemical ChemComp-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe / Feature type: SUBJECT OF INVESTIGATION
#11: Chemical ChemComp-SY8 / 5-azanylpentan-2-one


Mass: 101.147 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H11NO / Feature type: SUBJECT OF INVESTIGATION
#12: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn / 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: LRRC58-EloB/C-CDO1 in complex with NEDD8-CUL5-RBX2-ARIH2-Ub
Type: COMPLEX / Entity ID: #1-#9 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli, Trichoplusia ni
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 50.24 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.1_5286model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 847022 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 90.99 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002915327
ELECTRON MICROSCOPYf_angle_d0.542420720
ELECTRON MICROSCOPYf_chiral_restr0.03952321
ELECTRON MICROSCOPYf_plane_restr0.00372661
ELECTRON MICROSCOPYf_dihedral_angle_d4.98282055

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