+Open data
-Basic information
Entry | Database: PDB / ID: 8yvg | |||||||||
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Title | canine immunoproteasome 20S subunit in complex with compound 1 | |||||||||
Components | (Proteasome subunit ...) x 14 | |||||||||
Keywords | HYDROLASE / Inhibitor / Complex / Immunoproteasome | |||||||||
Function / homology | Function and homology information Activation of NF-kappaB in B cells / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Cross-presentation of soluble exogenous antigens (endosomes) / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SCF(Skp2)-mediated degradation of p27/p21 / Degradation of beta-catenin by the destruction complex / Downstream TCR signaling ...Activation of NF-kappaB in B cells / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Cross-presentation of soluble exogenous antigens (endosomes) / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SCF(Skp2)-mediated degradation of p27/p21 / Degradation of beta-catenin by the destruction complex / Downstream TCR signaling / Separation of Sister Chromatids / FCERI mediated NF-kB activation / Autodegradation of the E3 ubiquitin ligase COP1 / Regulation of ornithine decarboxylase (ODC) / ABC-family proteins mediated transport / AUF1 (hnRNP D0) binds and destabilizes mRNA / Asymmetric localization of PCP proteins / Degradation of AXIN / Degradation of DVL / Hedgehog ligand biogenesis / Dectin-1 mediated noncanonical NF-kB signaling / CLEC7A (Dectin-1) signaling / Degradation of GLI1 by the proteasome / GLI3 is processed to GLI3R by the proteasome / Hedgehog 'on' state / Regulation of RAS by GAPs / NIK-->noncanonical NF-kB signaling / UCH proteinases / Ub-specific processing proteases / Assembly of the pre-replicative complex / Orc1 removal from chromatin / CDK-mediated phosphorylation and removal of Cdc6 / G2/M Checkpoints / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Ubiquitin-dependent degradation of Cyclin D / The role of GTSE1 in G2/M progression after G2 checkpoint / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Regulation of RUNX2 expression and activity / Regulation of RUNX3 expression and activity / Regulation of PTEN stability and activity / Neddylation / Interleukin-1 signaling / KEAP1-NFE2L2 pathway / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Antigen processing: Ubiquitination & Proteasome degradation / TNFR2 non-canonical NF-kB pathway / MAPK6/MAPK4 signaling / spermatoproteasome complex / proteasome core complex / immune system process / fat cell differentiation / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteasomal protein catabolic process / T cell proliferation / proteolysis involved in protein catabolic process / P-body / response to virus / cell morphogenesis / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / postsynapse / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Canis lupus familiaris (dog) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2 Å | |||||||||
Authors | Kashima, A. / Arai, Y. | |||||||||
Funding support | 1items
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Citation | Journal: Bioorg Med Chem / Year: 2024 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: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8yvg.cif.gz | 1.2 MB | Display | PDBx/mmCIF format |
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PDB format | pdb8yvg.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 8yvg.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8yvg_validation.pdf.gz | 1.6 MB | Display | wwPDB validaton report |
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Full document | 8yvg_full_validation.pdf.gz | 1.6 MB | Display | |
Data in XML | 8yvg_validation.xml.gz | 144.9 KB | Display | |
Data in CIF | 8yvg_validation.cif.gz | 237.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/yv/8yvg ftp://data.pdbj.org/pub/pdb/validation_reports/yv/8yvg | HTTPS FTP |
-Related structure data
Related structure data | 39600MC 8ypkC 8ysxC 8yvpC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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Noncrystallographic symmetry (NCS) | NCS domain:
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-Components
-Proteasome subunit ... , 14 types, 28 molecules MHNIOZPbQJTVUYCDSXGLKRFAEBWa
#1: Protein | Mass: 26435.977 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0NHD1 #2: Protein | Mass: 27911.912 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0TD63 #3: Protein | Mass: 29524.791 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0TIY6 #4: Protein | Mass: 25927.535 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0QRK5 #5: Protein | Mass: 28484.326 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0R9W7 #6: Protein | Mass: 22808.186 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0QE86 #7: Protein | Mass: 23002.922 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0M3N7 #8: Protein | Mass: 22730.510 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) References: UniProt: Q5W416, proteasome endopeptidase complex #9: Protein | Mass: 26431.156 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0N5D2 #10: Protein | Mass: 29523.564 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8I3PML0 #11: Protein | Mass: 27418.434 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0SR54 #12: Protein | Mass: 21235.891 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: Q5W412 #13: Protein | Mass: 29317.428 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0SLB3 #14: Protein | Mass: 29191.088 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0MRG6 |
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-Non-polymers , 1 types, 4 molecules
#15: Chemical | ChemComp-A1L0C / [( Mass: 308.184 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H25BN4O3 / Feature type: SUBJECT OF INVESTIGATION |
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-Details
Has ligand of interest | Y |
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Has protein modification | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: 20S immunoproteasome / Type: COMPLEX / Entity ID: #10, #1-#5, #11, #6-#7, #14, #9, #13 / Source: NATURAL |
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Source (natural) | Organism: Canis lupus familiaris (dog) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-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: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 91.875 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-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 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 896501 / Symmetry type: POINT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement | Resolution: 2→172.64 Å / Cor.coef. Fo:Fc: 0.849 / SU B: 4.167 / SU ML: 0.101 / ESU R: 0.168 Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
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Solvent computation | Solvent model: PARAMETERS FOR MASK CACLULATION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 44.183 Å2
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Refinement step | Cycle: 1 / Total: 47948 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
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