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Yorodumi- PDB-8r5h: Ubiquitin ligation to neosubstrate by a cullin-RING E3 ligase & C... -
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-Basic information
Entry | Database: PDB / ID: 8r5h | ||||||
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Title | Ubiquitin ligation to neosubstrate by a cullin-RING E3 ligase & Cdc34: NEDD8-CUL2-RBX1-ELOB/C-VHL-MZ1 with trapped UBE2R2~donor UB-BRD4 BD2 | ||||||
Components |
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Keywords | LIGASE / CUL2 / VHL / ELOBC / BRD4 / MZ1 / PROTAC / Ubiquitin / Ubiquitin Ligase / Monoubiquitylation / NEDD8 / RBX1 | ||||||
Function / homology | Function and homology information regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling ...regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / positive regulation of protein autoubiquitination / protein neddylation / Replication of the SARS-CoV-1 genome / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / negative regulation of response to oxidative stress / ubiquitin-ubiquitin ligase activity / Cul4A-RING E3 ubiquitin ligase complex / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / negative regulation of type I interferon production / Cul4B-RING E3 ubiquitin ligase complex / intracellular non-membrane-bounded organelle / ubiquitin ligase complex scaffold activity / E2 ubiquitin-conjugating enzyme / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / SUMOylation of ubiquitinylation proteins / Prolactin receptor signaling / negative regulation of transcription elongation by RNA polymerase II / protein monoubiquitination / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / ubiquitin conjugating enzyme activity / cullin family protein binding / RNA polymerase II C-terminal domain binding / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of DNA damage checkpoint / P-TEFb complex binding / ubiquitin-like ligase-substrate adaptor activity / negative regulation by host of viral transcription / 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 / Nuclear events stimulated by ALK signaling in cancer / negative regulation of signal transduction / positive regulation of T-helper 17 cell lineage commitment / protein K48-linked ubiquitination / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / negative regulation of TORC1 signaling / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / positive regulation of TORC1 signaling / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / RNA Polymerase II Pre-transcription Events / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1-dependent activation of IRF3/IRF7 / positive regulation of G2/M transition of mitotic cell cycle / APC/C:Cdc20 mediated degradation of Cyclin B / p75NTR recruits signalling complexes / Downregulation of ERBB4 signaling / T cell activation / histone reader activity / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / TRAF6-mediated induction of TAK1 complex within TLR4 complex / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / Pexophagy / Regulation of innate immune responses to cytosolic DNA / InlA-mediated entry of Listeria monocytogenes into host cells / VLDLR internalisation and degradation / regulation of cellular response to insulin stimulus / Downregulation of ERBB2:ERBB3 signaling / NF-kB is activated and signals survival / NRIF signals cell death from the nucleus / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.44 Å | ||||||
Authors | Liwocha, J. / Prabu, J.R. / Kleiger, G. / Schulman, B.A. | ||||||
Funding support | Germany, 1items
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Citation | Journal: Mol Cell / Year: 2024 Title: Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting. Authors: Jerry Li / Nicholas Purser / Joanna Liwocha / Daniel C Scott / Holly A Byers / Barbara Steigenberger / Spencer Hill / Ishita Tripathi-Giesgen / Trent Hinkle / Fynn M Hansen / J Rajan Prabu / ...Authors: Jerry Li / Nicholas Purser / Joanna Liwocha / Daniel C Scott / Holly A Byers / Barbara Steigenberger / Spencer Hill / Ishita Tripathi-Giesgen / Trent Hinkle / Fynn M Hansen / J Rajan Prabu / Senthil K Radhakrishnan / Donald S Kirkpatrick / Kurt M Reichermeier / Brenda A Schulman / Gary Kleiger / Abstract: Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. ...Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. Substrates are recognized by substrate receptors, such as Fbox or BCbox proteins. Meanwhile, CRLs employ assorted ubiquitin-carrying enzymes (UCEs, which are a collection of E2 and ARIH-family E3s) specialized for either initial substrate ubiquitylation (priming) or forging poly-ubiquitin chains. We discovered specific human CRL-UCE pairings governing substrate priming. The results reveal pairing of CUL2-based CRLs and UBE2R-family UCEs in cells, essential for efficient PROTAC-induced neo-substrate degradation. Despite UBE2R2's intrinsic programming to catalyze poly-ubiquitylation, CUL2 employs this UCE for geometrically precise PROTAC-dependent ubiquitylation of a neo-substrate and for rapid priming of substrates recruited to diverse receptors. Cryo-EM structures illuminate how CUL2-based CRLs engage UBE2R2 to activate substrate ubiquitylation. Thus, pairing with a specific UCE overcomes E2 catalytic limitations to drive substrate ubiquitylation and targeted protein degradation. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8r5h.cif.gz | 274.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8r5h.ent.gz | 210.8 KB | Display | PDB format |
PDBx/mmJSON format | 8r5h.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8r5h_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8r5h_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8r5h_validation.xml.gz | 57.1 KB | Display | |
Data in CIF | 8r5h_validation.cif.gz | 85.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/r5/8r5h ftp://data.pdbj.org/pub/pdb/validation_reports/r5/8r5h | HTTPS FTP |
-Related structure data
Related structure data | 18915MC 8q7rC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 8 types, 8 molecules ARCUDFGH
#1: Protein | Mass: 87098.930 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CUL2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q13617 |
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#2: Protein | Mass: 11945.547 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1, RNF75, ROC1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62877 |
#3: Protein | Mass: 25853.664 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: UBE2R2, CDC34B, UBC3B / Production host: Escherichia coli BL21 (bacteria) References: UniProt: Q712K3, E2 ubiquitin-conjugating enzyme |
#4: Protein | Mass: 8519.778 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: UBC / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P0CG48 |
#5: Protein | 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: Escherichia coli BL21 (bacteria) / References: UniProt: Q15369 |
#6: Protein | Mass: 13256.254 Da / Num. of mol.: 1 / Mutation: C356A C357A K368C C391A C429A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: O60885 |
#7: Protein | 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 BL21 (bacteria) / References: UniProt: Q15370 |
#8: Protein | Mass: 18558.162 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P40337 |
-Non-polymers , 3 types, 5 molecules
#9: Chemical | #10: Chemical | ChemComp-SY8 / | #11: Chemical | ChemComp-759 / ( | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2600 nm / Nominal defocus min: 600 nm |
Image recording | Electron dose: 66 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 148402 / Symmetry type: POINT | ||||||||||||||||||||||||
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