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Open data
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Basic information
Entry | Database: PDB / ID: 8ypk | ||||||
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Title | mouse proteasome 20S subunit in complex with compound 1 | ||||||
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![]() | HYDROLASE / Inhibitor / complex / Proteasome | ||||||
Function / homology | ![]() Regulation of ornithine decarboxylase (ODC) / Cross-presentation of soluble exogenous antigens (endosomes) / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SCF(Skp2)-mediated degradation of p27/p21 / Assembly of the pre-replicative complex ...Regulation of ornithine decarboxylase (ODC) / Cross-presentation of soluble exogenous antigens (endosomes) / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SCF(Skp2)-mediated degradation of p27/p21 / Assembly of the pre-replicative complex / CDK-mediated phosphorylation and removal of Cdc6 / Degradation of AXIN / Autodegradation of the E3 ubiquitin ligase COP1 / G2/M Checkpoints / Asymmetric localization of PCP proteins / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / Regulation of RUNX3 expression and activity / Regulation of RAS by GAPs / Regulation of PTEN stability and activity / Regulation of RUNX2 expression and activity / Degradation of GLI1 by the proteasome / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Degradation of DVL / UCH proteinases / Orc1 removal from chromatin / Dectin-1 mediated noncanonical NF-kB signaling / NIK-->noncanonical NF-kB signaling / Hedgehog ligand biogenesis / TNFR2 non-canonical NF-kB pathway / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Hedgehog 'on' state / Degradation of beta-catenin by the destruction complex / Activation of NF-kappaB in B cells / The role of GTSE1 in G2/M progression after G2 checkpoint / FCERI mediated NF-kB activation / CLEC7A (Dectin-1) signaling / Interleukin-1 signaling / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Separation of Sister Chromatids / Downstream TCR signaling / KEAP1-NFE2L2 pathway / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / ABC-family proteins mediated transport / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Ub-specific processing proteases / proteasome core complex / immune system process / myofibril / NF-kappaB binding / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / skeletal muscle tissue development / negative regulation of inflammatory response to antigenic stimulus / : / Neutrophil degranulation / sarcomere / proteasome complex / ciliary basal body / proteolysis involved in protein catabolic process / lipopolysaccharide binding / P-body / protein catabolic process / response to virus / response to organic cyclic compound / nuclear matrix / peptidase activity / positive regulation of NF-kappaB transcription factor activity / postsynapse / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / response to oxidative stress / nuclear body / ribosome / centrosome / ubiquitin protein ligase binding / synapse / mitochondrion / proteolysis / RNA binding / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å | ||||||
![]() | Kashima, A. / Arai, Y. | ||||||
Funding support | 1items
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![]() | ![]() Title: Optimization of α-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual inhibitor. Authors: Yuuki Arai / Hiroaki Shitama / Masahito Yamagishi / Satoshi Ono / Akiko Kashima / Masahiro Hiraizumi / Naoki Tsuda / Koushirou Katayama / Kouji Tanaka / Yuzo Koda / Sayuka Kato / Kei Sakata ...Authors: Yuuki Arai / Hiroaki Shitama / Masahito Yamagishi / Satoshi Ono / Akiko Kashima / Masahiro Hiraizumi / Naoki Tsuda / Koushirou Katayama / Kouji Tanaka / Yuzo Koda / Sayuka Kato / Kei Sakata / Osamu Nureki / Hiroshi Miyazaki / ![]() Abstract: The immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising ...The immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit β5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over β5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of α-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor 19. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with 19 explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that 19 is orally bioavailable and shows promise as potential treatment for autoimmune diseases. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 1.2 MB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.7 MB | Display | ![]() |
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Full document | ![]() | 1.8 MB | Display | |
Data in XML | ![]() | 142.3 KB | Display | |
Data in CIF | ![]() | 229.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 39482MC ![]() 8ysxC ![]() 8yvgC ![]() 8yvpC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Noncrystallographic symmetry (NCS) | NCS domain:
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Components
-Proteasome subunit beta type- ... , 7 types, 14 molecules AFTVSXDCBEWaYU
#1: Protein | Mass: 21913.814 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: Q60692, proteasome endopeptidase complex #5: Protein | Mass: 22935.377 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #6: Protein | Mass: 26405.182 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #7: Protein | Mass: 22453.441 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: O55234, proteasome endopeptidase complex #12: Protein | Mass: 25280.010 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: P70195, proteasome endopeptidase complex #13: Protein | Mass: 29143.053 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #14: Protein | Mass: 22988.895 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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-Proteasome subunit alpha type- ... , 7 types, 14 molecules PbNIRKJQLGHMOZ
#2: Protein | Mass: 25955.549 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #3: Protein | Mass: 27897.887 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #4: Protein | Mass: 27405.434 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #8: Protein | Mass: 28442.248 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #9: Protein | Mass: 29586.576 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #10: Protein | Mass: 26435.977 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #11: Protein | Mass: 29512.807 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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-Non-polymers , 1 types, 4 molecules
#15: Chemical | ChemComp-A1L0C / [( Mass: 410.296 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H33BN5O5 / Feature type: SUBJECT OF INVESTIGATION |
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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 |
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Sample preparation
Component | Name: 20S proteasome / Type: COMPLEX / Entity ID: #1-#6, #8-#14 / Source: NATURAL |
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Source (natural) | Organism: ![]() ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 49.692 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
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Processing
EM software | Name: REFMAC / Version: 5.8.0258 / Category: model refinement | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 25513 / Symmetry type: POINT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement | Resolution: 2.7→172.54 Å / Cor.coef. Fo:Fc: 0.838 / SU B: 15.334 / SU ML: 0.281 / ESU R: 0.48 Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
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Solvent computation | Solvent model: PARAMETERS FOR MASK CACLULATION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 50.569 Å2
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Refinement step | Cycle: 1 / Total: 47992 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
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