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Yorodumi- EMDB-7010: Cryo-EM structure of human immunoproteasome with a novel noncompe... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-7010 | |||||||||
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Title | Cryo-EM structure of human immunoproteasome with a novel noncompetitive inhibitor that selectively inhibits activated lymphocytes | |||||||||
Map data | human immunoproteasome with a novel noncompetitive inhibitor | |||||||||
Sample |
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Keywords | inhibitor / complex / immunoproteasome / HYDROLASE-HYDROLASE INHIBITOR complex | |||||||||
Function / homology | Function and homology information regulation of cysteine-type endopeptidase activity / spermatoproteasome complex / purine ribonucleoside triphosphate binding / regulation of endopeptidase activity / Regulation of ornithine decarboxylase (ODC) / proteasome core complex / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / immune system process / myofibril ...regulation of cysteine-type endopeptidase activity / spermatoproteasome complex / purine ribonucleoside triphosphate binding / regulation of endopeptidase activity / Regulation of ornithine decarboxylase (ODC) / proteasome core complex / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / immune system process / myofibril / fat cell differentiation / antigen processing and presentation / humoral immune response / NF-kappaB binding / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / T cell proliferation / negative regulation of inflammatory response to antigenic stimulus / : / sarcomere / proteasome complex / Regulation of activated PAK-2p34 by proteasome mediated degradation / ciliary basal body / proteolysis involved in protein catabolic process / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / TNFR2 non-canonical NF-kB pathway / Vpu mediated degradation of CD4 / Assembly of the pre-replicative complex / Degradation of DVL / CDK-mediated phosphorylation and removal of Cdc6 / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Dectin-1 mediated noncanonical NF-kB signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Hh mutants are degraded by ERAD / lipopolysaccharide binding / SCF(Skp2)-mediated degradation of p27/p21 / Degradation of AXIN / Degradation of GLI1 by the proteasome / Activation of NF-kappaB in B cells / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / G2/M Checkpoints / Vif-mediated degradation of APOBEC3G / Autodegradation of the E3 ubiquitin ligase COP1 / Hedgehog 'on' state / Regulation of RUNX3 expression and activity / P-body / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / Orc1 removal from chromatin / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / MAPK6/MAPK4 signaling / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / response to virus / Degradation of beta-catenin by the destruction complex / cell morphogenesis / ABC-family proteins mediated transport / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / response to organic cyclic compound / CLEC7A (Dectin-1) signaling / Regulation of expression of SLITs and ROBOs / FCERI mediated NF-kB activation / nuclear matrix / Regulation of PTEN stability and activity / Interleukin-1 signaling / Regulation of RAS by GAPs / Separation of Sister Chromatids / Regulation of RUNX2 expression and activity / The role of GTSE1 in G2/M progression after G2 checkpoint / UCH proteinases / KEAP1-NFE2L2 pathway / Interferon alpha/beta signaling / Antigen processing: Ubiquitination & Proteasome degradation / regulation of inflammatory response / Downstream TCR signaling / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Neddylation / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / endopeptidase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / secretory granule lumen / ficolin-1-rich granule lumen / postsynapse / ribosome / Ub-specific processing proteases / intracellular membrane-bounded organelle / centrosome / ubiquitin protein ligase binding / synapse Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.8 Å | |||||||||
Authors | Li H / Santos R | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Nat Commun / Year: 2017 Title: Structure of human immunoproteasome with a reversible and noncompetitive inhibitor that selectively inhibits activated lymphocytes. Authors: Ruda de Luna Almeida Santos / Lin Bai / Pradeep K Singh / Naoka Murakami / Hao Fan / Wenhu Zhan / Yingrong Zhu / Xiuju Jiang / Kaiming Zhang / Jean Pierre Assker / Carl F Nathan / Huilin Li ...Authors: Ruda de Luna Almeida Santos / Lin Bai / Pradeep K Singh / Naoka Murakami / Hao Fan / Wenhu Zhan / Yingrong Zhu / Xiuju Jiang / Kaiming Zhang / Jean Pierre Assker / Carl F Nathan / Huilin Li / Jamil Azzi / Gang Lin / Abstract: Proteasome inhibitors benefit patients with multiple myeloma and B cell-dependent autoimmune disorders but exert toxicity from inhibition of proteasomes in other cells. Toxicity should be minimized ...Proteasome inhibitors benefit patients with multiple myeloma and B cell-dependent autoimmune disorders but exert toxicity from inhibition of proteasomes in other cells. Toxicity should be minimized by reversible inhibition of the immunoproteasome β5i subunit while sparing the constitutive β5c subunit. Here we report β5i-selective inhibition by asparagine-ethylenediamine (AsnEDA)-based compounds and present the high-resolution cryo-EM structural analysis of the human immunoproteasome. Despite inhibiting noncompetitively, an AsnEDA inhibitor binds the active site. Hydrophobic interactions are accompanied by hydrogen bonding with β5i and β6 subunits. The inhibitors are far more cytotoxic for myeloma and lymphoma cell lines than for hepatocarcinoma or non-activated lymphocytes. They block human B-cell proliferation and promote apoptotic cell death selectively in antibody-secreting B cells, and to a lesser extent in activated human T cells. Reversible, β5i-selective inhibitors may be useful for treatment of diseases involving activated or neoplastic B cells or activated T cells. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_7010.map.gz | 5.5 MB | EMDB map data format | |
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Header (meta data) | emd-7010-v30.xml emd-7010.xml | 24.5 KB 24.5 KB | Display Display | EMDB header |
Images | emd_7010.png | 201.5 KB | ||
Filedesc metadata | emd-7010.cif.gz | 7.4 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-7010 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-7010 | HTTPS FTP |
-Validation report
Summary document | emd_7010_validation.pdf.gz | 402.4 KB | Display | EMDB validaton report |
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Full document | emd_7010_full_validation.pdf.gz | 402 KB | Display | |
Data in XML | emd_7010_validation.xml.gz | 6.2 KB | Display | |
Data in CIF | emd_7010_validation.cif.gz | 7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-7010 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-7010 | HTTPS FTP |
-Related structure data
Related structure data | 6avoMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_7010.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | human immunoproteasome with a novel noncompetitive inhibitor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.2 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
+Entire : human immunoproteasome with a novel noncompetitive inhibitor that...
+Supramolecule #1: human immunoproteasome with a novel noncompetitive inhibitor that...
+Macromolecule #1: Proteasome subunit beta type-9
+Macromolecule #2: Proteasome subunit beta type-10
+Macromolecule #3: Proteasome subunit beta type-8
+Macromolecule #4: Proteasome subunit alpha type-1
+Macromolecule #5: Proteasome subunit alpha type-5
+Macromolecule #6: Proteasome subunit alpha type-7
+Macromolecule #7: Proteasome subunit alpha type-3
+Macromolecule #8: Proteasome subunit alpha type-6
+Macromolecule #9: Proteasome subunit alpha type-4
+Macromolecule #10: Proteasome subunit alpha type-2
+Macromolecule #11: Proteasome subunit beta type-1
+Macromolecule #12: Proteasome subunit beta type-2
+Macromolecule #13: Proteasome subunit beta type-3
+Macromolecule #14: Proteasome subunit beta type-4
+Macromolecule #15: N~1~-{2-[([1,1'-biphenyl]-3-carbonyl)amino]ethyl}-N~4~-tert-butyl...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | JEOL 3200FS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 1.4) / Number images used: 75017 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |