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Open data
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Basic information
| Entry | Database: EMDB / ID: EMD-4146 | ||||||||||||
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| Title | Human 26S proteasome in complex with Oprozomib | ||||||||||||
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Keywords | proteasome / oprozomib / ups / drug-binding / Hydrolase | ||||||||||||
| Function / homology | Function and homology informationthyrotropin-releasing hormone receptor binding / nuclear proteasome complex / host-mediated perturbation of viral transcription / positive regulation of inclusion body assembly / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / meiosis I / proteasome accessory complex / purine ribonucleoside triphosphate binding / integrator complex ...thyrotropin-releasing hormone receptor binding / nuclear proteasome complex / host-mediated perturbation of viral transcription / positive regulation of inclusion body assembly / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / meiosis I / proteasome accessory complex / purine ribonucleoside triphosphate binding / integrator complex / proteasome regulatory particle / CD8-positive, alpha-beta T cell differentiation / thymic T cell selection / CD8-positive, alpha-beta T cell homeostasis / cytosolic proteasome complex / positive regulation of proteasomal protein catabolic process / proteasome-activating activity / Antigen processing: Ub, ATP-independent proteasomal degradation / proteasome regulatory particle, lid subcomplex / proteasome regulatory particle, base subcomplex / T-helper 1 cell differentiation / negative regulation of regulatory T cell differentiation / cellular response to type I interferon / protein K63-linked deubiquitination / metal-dependent deubiquitinase activity / negative regulation of programmed cell death / Regulation of ornithine decarboxylase (ODC) / proteasome core complex / Proteasome assembly / T-helper 17 cell differentiation / Cross-presentation of soluble exogenous antigens (endosomes) / transcription factor binding / K63-linked deubiquitinase activity / Somitogenesis / Homologous DNA Pairing and Strand Exchange / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / flagellated sperm motility / Resolution of D-loop Structures through Holliday Junction Intermediates / proteasome binding / Impaired BRCA2 binding to RAD51 / regulation of protein catabolic process / myofibril / AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274) / GSK3B-mediated proteasomal degradation of PD-L1(CD274) / SPOP-mediated proteasomal degradation of PD-L1(CD274) / proteasomal ubiquitin-independent protein catabolic process / positive regulation of RNA polymerase II transcription preinitiation complex assembly / Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide / general transcription initiation factor binding / proteasome storage granule / Presynaptic phase of homologous DNA pairing and strand exchange / protein deubiquitination / polyubiquitin modification-dependent protein binding / proteasome endopeptidase complex / NF-kappaB binding / proteasome core complex, beta-subunit complex / endopeptidase activator activity / threonine-type endopeptidase activity / mRNA export from nucleus / proteasome core complex, alpha-subunit complex / proteasome assembly / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / immune system process / regulation of G1/S transition of mitotic cell cycle / enzyme regulator activity / ERAD pathway / ciliary tip / response to type II interferon / positive regulation of interleukin-2 production / inclusion body / regulation of proteasomal protein catabolic process / TBP-class protein binding / : / proteasome complex / stem cell differentiation / sarcomere / proteasomal protein catabolic process / Regulation of activated PAK-2p34 by proteasome mediated degradation / sperm end piece / ubiquitin binding / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / negative regulation of inflammatory response to antigenic stimulus / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / lipopolysaccharide binding / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / AUF1 (hnRNP D0) binds and destabilizes mRNA / TNFR2 non-canonical NF-kB pathway / Assembly of the pre-replicative complex / Vpu mediated degradation of CD4 / P-body / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Dectin-1 mediated noncanonical NF-kB signaling / Degradation of DVL Similarity search - Function | ||||||||||||
| Biological species | Homo sapiens (human) / Synthetic construct (others) | ||||||||||||
| Method | single particle reconstruction / cryo EM / Resolution: 3.8 Å | ||||||||||||
Authors | Haselbach D / Schrader J | ||||||||||||
| Funding support | Germany, 3 items
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Citation | Journal: Nat Commun / Year: 2017Title: Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs. Authors: David Haselbach / Jil Schrader / Felix Lambrecht / Fabian Henneberg / Ashwin Chari / Holger Stark / ![]() Abstract: The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of ...The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP). Structurally, the energy barrier created by Oprozomib triggers a long-range allosteric regulation, resulting in the stabilization of a non-productive state. Thereby, the chemical drug-binding signal is converted, propagated and amplified into structural changes over a distance of more than 150 Å from the proteolytic site to the ubiquitin receptor Rpn10. The direct visualization of changes in conformational dynamics upon drug binding allows new ways to screen and develop future allosteric proteasome inhibitors. | ||||||||||||
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Structure visualization
| Movie |
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| Structure viewer | EM map: SurfView Molmil Jmol/JSmol |
| Supplemental images |
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Downloads & links
-EMDB archive
| Map data | emd_4146.map.gz | 13.9 MB | EMDB map data format | |
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| Header (meta data) | emd-4146-v30.xml emd-4146.xml | 64.1 KB 64.1 KB | Display Display | EMDB header |
| Images | emd_4146.png | 150.4 KB | ||
| Filedesc metadata | emd-4146.cif.gz | 14.6 KB | ||
| Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-4146 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-4146 | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 5m32MC M: atomic model generated by this map C: citing same article ( |
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| Similar structure data | |
| EM raw data | EMPIAR-10166 (Title: human 26S proteasome bound to the chemotherapeutic OprozomibData size: 100.5 Data #1: Particle stack of aligned, summed and dose weighted particle images from the human 26S proteasome bound to oprozomib. [picked particles - single frame - processed]) |
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Links
| EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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| Related items in Molecule of the Month |
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Map
| File | Download / File: emd_4146.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Voxel size | X=Y=Z: 1.27 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Density |
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| Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
+Entire : human 26S proteasome in complex with oprozomib
+Supramolecule #1: human 26S proteasome in complex with oprozomib
+Supramolecule #2: human 26S proteasome
+Supramolecule #3: bound oprozomib
+Macromolecule #1: Proteasome subunit alpha type-2
+Macromolecule #2: Proteasome subunit alpha type-4
+Macromolecule #3: Proteasome subunit alpha type-7
+Macromolecule #4: Proteasome subunit alpha type-5
+Macromolecule #5: Proteasome subunit alpha type-1
+Macromolecule #6: Proteasome subunit alpha type-3
+Macromolecule #7: Proteasome subunit alpha type-6
+Macromolecule #8: Proteasome subunit beta type-7
+Macromolecule #9: Proteasome subunit beta type-3
+Macromolecule #10: Proteasome subunit beta type-2
+Macromolecule #11: Proteasome subunit beta type-5
+Macromolecule #12: Proteasome subunit beta type-1
+Macromolecule #13: Proteasome subunit beta type-4
+Macromolecule #14: Proteasome subunit beta type-6
+Macromolecule #15: Proteasome subunit alpha type-7
+Macromolecule #16: Proteasome subunit alpha type-1
+Macromolecule #17: 26S protease regulatory subunit 7
+Macromolecule #18: 26S protease regulatory subunit 4
+Macromolecule #19: 26S protease regulatory subunit 6B
+Macromolecule #20: 26S protease regulatory subunit 10B
+Macromolecule #21: 26S protease regulatory subunit 6A
+Macromolecule #22: 26S protease regulatory subunit 8
+Macromolecule #23: 26S proteasome non-ATPase regulatory subunit 1
+Macromolecule #24: 26S proteasome non-ATPase regulatory subunit 3
+Macromolecule #25: 26S proteasome non-ATPase regulatory subunit 12
+Macromolecule #26: 26S proteasome non-ATPase regulatory subunit 11
+Macromolecule #27: 26S proteasome non-ATPase regulatory subunit 6
+Macromolecule #28: 26S proteasome non-ATPase regulatory subunit 7
+Macromolecule #29: 26S proteasome non-ATPase regulatory subunit 13
+Macromolecule #30: 26S proteasome non-ATPase regulatory subunit 4
+Macromolecule #31: 26S proteasome non-ATPase regulatory subunit 14
+Macromolecule #32: 26S proteasome non-ATPase regulatory subunit 8
+Macromolecule #33: 26S proteasome complex subunit SEM1
+Macromolecule #34: bound Oprozomib
+Macromolecule #35: ADENOSINE-5'-DIPHOSPHATE
-Experimental details
-Structure determination
| Method | cryo EM |
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Processing | single particle reconstruction |
| Aggregation state | particle |
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Sample preparation
| Buffer | pH: 6.5 Component:
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| Grid | Model: Quantifoil / Material: COPPER / Mesh: 200 / Support film - #0 - Film type ID: 1 / Support film - #0 - Material: CARBON / Support film - #0 - topology: HOLEY / Support film - #1 - Film type ID: 2 / Support film - #1 - Material: CARBON / Support film - #1 - topology: CONTINUOUS | ||||||||||||||||||
| Vitrification | Cryogen name: ETHANE / Chamber humidity: 72 % / Chamber temperature: 4 K / Instrument: LEICA EM GP / Details: blot with sensor. |
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Electron microscopy
| Microscope | FEI TITAN KRIOS |
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| Specialist optics | Spherical aberration corrector: Microscope is equipped with Cs corrector |
| Image recording | Film or detector model: FEI FALCON II (4k x 4k) / Detector mode: OTHER / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Average exposure time: 1.0 sec. / Average electron dose: 2.0 e/Å2 |
| Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
| Electron optics | C2 aperture diameter: 70.0 µm / Calibrated magnification: 110236 / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 0.0001 mm / Nominal defocus max: 8.4 µm / Nominal defocus min: 0.3 µm / Nominal magnification: 59000 |
| Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
| Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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About Yorodumi



Keywords
Homo sapiens (human)
Authors
Germany, 3 items
Citation
UCSF Chimera






















Z (Sec.)
Y (Row.)
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