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Yorodumi- PDB-6avo: Cryo-EM structure of human immunoproteasome with a novel noncompe... -
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-Basic information
Entry | Database: PDB / ID: 6avo | ||||||
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Title | Cryo-EM structure of human immunoproteasome with a novel noncompetitive inhibitor that selectively inhibits activated lymphocytes | ||||||
Components |
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Keywords | HYDROLASE/HYDROLASE INHIBITOR / 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 / proteasome core complex / Regulation of ornithine decarboxylase (ODC) / 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 / proteasome core complex / Regulation of ornithine decarboxylase (ODC) / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / immune system process / myofibril / fat cell differentiation / humoral immune response / antigen processing and presentation / 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 / response to organonitrogen compound / sarcomere / proteasome complex / proteolysis involved in protein catabolic process / Regulation of activated PAK-2p34 by proteasome mediated degradation / ciliary basal body / 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 / Assembly of the pre-replicative complex / Vpu mediated degradation of CD4 / Degradation of DVL / 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 / Degradation of AXIN / lipopolysaccharide binding / Degradation of GLI1 by the proteasome / Activation of NF-kappaB in B cells / Defective CFTR causes cystic fibrosis / Hedgehog ligand biogenesis / Negative regulation of NOTCH4 signaling / G2/M Checkpoints / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Autodegradation of the E3 ubiquitin ligase COP1 / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / Regulation of RUNX3 expression and activity / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / MAPK6/MAPK4 signaling / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / P-body / response to virus / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / ABC-family proteins mediated transport / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cell morphogenesis / response to organic cyclic compound / CDK-mediated phosphorylation and removal of Cdc6 / CLEC7A (Dectin-1) signaling / SCF(Skp2)-mediated degradation of p27/p21 / Regulation of expression of SLITs and ROBOs / nuclear matrix / FCERI mediated NF-kB activation / Regulation of PTEN stability and activity / Interleukin-1 signaling / Orc1 removal from chromatin / Regulation of RAS by GAPs / Separation of Sister Chromatids / Regulation of RUNX2 expression and activity / UCH proteinases / The role of GTSE1 in G2/M progression after G2 checkpoint / KEAP1-NFE2L2 pathway / Interferon alpha/beta signaling / Antigen processing: Ubiquitination & Proteasome degradation / Downstream TCR signaling / Neddylation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / regulation of inflammatory response / postsynapse / proteasome-mediated ubiquitin-dependent protein catabolic process / secretory granule lumen / endopeptidase activity / ficolin-1-rich granule lumen / ribosome / Ub-specific processing proteases / intracellular membrane-bounded organelle / centrosome / synapse / ubiquitin protein ligase binding Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å | ||||||
Authors | Li, H. / Santos, R. / Bai, L. | ||||||
Funding support | United States, 1items
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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 | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6avo.cif.gz | 1 MB | Display | PDBx/mmCIF format |
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PDB format | pdb6avo.ent.gz | 856.8 KB | Display | PDB format |
PDBx/mmJSON format | 6avo.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/av/6avo ftp://data.pdbj.org/pub/pdb/validation_reports/av/6avo | HTTPS FTP |
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-Related structure data
Related structure data | 7010MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Proteasome subunit beta type- ... , 7 types, 14 molecules AFBECDSXTVUYWa
#1: Protein | Mass: 21295.000 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P28065, proteasome endopeptidase complex #2: Protein | Mass: 24674.248 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P40306, proteasome endopeptidase complex #3: Protein | Mass: 22685.633 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P28062, proteasome endopeptidase complex #11: Protein | Mass: 23578.986 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P20618, proteasome endopeptidase complex #12: Protein | Mass: 22864.277 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P49721, proteasome endopeptidase complex #13: Protein | Mass: 22972.896 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P49720, proteasome endopeptidase complex #14: Protein | Mass: 24414.740 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P28070, proteasome endopeptidase complex |
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-Proteasome subunit alpha type- ... , 7 types, 14 molecules GLHMINJQKROZPb
#4: Protein | Mass: 29595.627 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P25786, proteasome endopeptidase complex #5: Protein | Mass: 26435.977 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P28066, proteasome endopeptidase complex #6: Protein | Mass: 27929.891 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: O14818, proteasome endopeptidase complex #7: Protein | Mass: 28469.252 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P25788, proteasome endopeptidase complex #8: Protein | Mass: 27432.459 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P60900, proteasome endopeptidase complex #9: Protein | Mass: 29525.842 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P25789, proteasome endopeptidase complex #10: Protein | Mass: 25927.535 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P25787, proteasome endopeptidase complex |
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-Non-polymers , 1 types, 2 molecules
#15: Chemical |
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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 |
-Sample preparation
Component | Name: human immunoproteasome with a novel noncompetitive inhibitor that selectively inhibits activated lymphocytes Type: COMPLEX / Entity ID: #1-#14 / Source: NATURAL |
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Source (natural) | Organism: Homo sapiens (human) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Microscopy | Model: JEOL 3200FS |
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Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.11.1_2575: / Classification: refinement | ||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 75017 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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