+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-39612 | |||||||||
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Title | canine immunoproteasome 20S subunit in complex with compound 1 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | inhibitor / complex / proteasome / hydrolase | |||||||||
Function / homology | Function and homology information 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 / Autodegradation of the E3 ubiquitin ligase COP1 / G2/M Checkpoints / Degradation of AXIN / 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 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Degradation of DVL / UCH proteinases / Orc1 removal from chromatin / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / 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 / sarcomere / Neutrophil degranulation / proteasome complex / ciliary basal body / proteolysis involved in protein catabolic process / lipopolysaccharide binding / P-body / response to virus / protein catabolic process / response to organic cyclic compound / nuclear matrix / positive regulation of NF-kappaB transcription factor activity / peptidase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / response to oxidative stress / postsynapse / nuclear body / ribosome / centrosome / ubiquitin protein ligase binding / synapse / mitochondrion / proteolysis / RNA binding / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.5 Å | |||||||||
Authors | Kashima A / Arai Y | |||||||||
Funding support | 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_39612.map.gz | 8.9 MB | EMDB map data format | |
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Header (meta data) | emd-39612-v30.xml emd-39612.xml | 28.2 KB 28.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_39612_fsc.xml | 9 KB | Display | FSC data file |
Images | emd_39612.png | 123.2 KB | ||
Masks | emd_39612_msk_1.map | 62.5 MB | Mask map | |
Filedesc metadata | emd-39612.cif.gz | 7.4 KB | ||
Others | emd_39612_half_map_1.map.gz emd_39612_half_map_2.map.gz | 47.4 MB 47.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-39612 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-39612 | HTTPS FTP |
-Validation report
Summary document | emd_39612_validation.pdf.gz | 921.3 KB | Display | EMDB validaton report |
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Full document | emd_39612_full_validation.pdf.gz | 920.8 KB | Display | |
Data in XML | emd_39612_validation.xml.gz | 14.6 KB | Display | |
Data in CIF | emd_39612_validation.cif.gz | 21.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39612 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39612 | HTTPS FTP |
-Related structure data
Related structure data | 8yvpMC 8ypkC 8ysxC 8yvgC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_39612.map.gz / Format: CCP4 / Size: 62.5 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: 1.15024 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_39612_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_39612_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_39612_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : 20S proteasome
+Supramolecule #1: 20S proteasome
+Macromolecule #1: Proteasome subunit beta type-7
+Macromolecule #2: Proteasome subunit beta type-5
+Macromolecule #3: Proteasome subunit alpha type-2
+Macromolecule #4: Proteasome subunit alpha type-3
+Macromolecule #5: Proteasome subunit alpha type-6
+Macromolecule #6: Proteasome subunit beta type-6
+Macromolecule #7: Proteasome subunit beta type-1
+Macromolecule #8: Proteasome subunit beta type-3
+Macromolecule #9: Proteasome subunit beta type-4
+Macromolecule #10: Proteasome subunit alpha type-5
+Macromolecule #11: Proteasome subunit beta type-2
+Macromolecule #12: Proteasome subunit alpha type-7
+Macromolecule #13: Proteasome subunit alpha type-1
+Macromolecule #14: Proteasome subunit alpha type-4
+Macromolecule #15: [(~{R})-cyclohexyl-[(1-cyclohexyl-1,2,3-triazol-4-yl)carbonylamin...
+Macromolecule #16: THREONINE
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 48.2 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |