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- PDB-6avo: Cryo-EM structure of human immunoproteasome with a novel noncompe... -

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Entry
Database: PDB / ID: 6avo
TitleCryo-EM structure of human immunoproteasome with a novel noncompetitive inhibitor that selectively inhibits activated lymphocytes
Components
  • (Proteasome subunit alpha type- ...) x 7
  • (Proteasome subunit beta type- ...) x 7
KeywordsHYDROLASE/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 / 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 / humoral immune response / NF-kappaB binding / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / antigen processing and presentation / threonine-type endopeptidase activity / T cell proliferation / negative regulation of inflammatory response to antigenic stimulus / : / response to organonitrogen compound / sarcomere / proteolysis involved in protein catabolic process / proteasome complex / 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 / Degradation of DVL / TNFR2 non-canonical NF-kB pathway / Assembly of the pre-replicative complex / Vpu mediated degradation of CD4 / proteasomal protein catabolic process / P-body / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Dectin-1 mediated noncanonical NF-kB signaling / Hh mutants are degraded by ERAD / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Degradation of GLI1 by the proteasome / lipopolysaccharide binding / Degradation of AXIN / Defective CFTR causes cystic fibrosis / Activation of NF-kappaB in B cells / Negative regulation of NOTCH4 signaling / Hedgehog ligand biogenesis / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Vif-mediated degradation of APOBEC3G / G2/M Checkpoints / Hedgehog 'on' state / Autodegradation of the E3 ubiquitin ligase COP1 / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / Regulation of RUNX3 expression and activity / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / response to virus / MAPK6/MAPK4 signaling / Degradation of beta-catenin by the destruction complex / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / ABC-family proteins mediated transport / 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 / Interleukin-1 signaling / Regulation of PTEN stability and activity / 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 / Ub-specific processing proteases / intracellular membrane-bounded organelle / centrosome / synapse
Similarity search - Function
Proteasome subunit alpha 1 / Aminohydrolase, N-terminal nucleophile (Ntn) domain / Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1 / Proteasome beta subunit, C-terminal / Proteasome beta subunits C terminal / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha6 / Proteasome subunit alpha5 ...Proteasome subunit alpha 1 / Aminohydrolase, N-terminal nucleophile (Ntn) domain / Glutamine Phosphoribosylpyrophosphate, subunit 1, domain 1 / Proteasome beta subunit, C-terminal / Proteasome beta subunits C terminal / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha6 / Proteasome subunit alpha5 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit / Proteasome beta-type subunit, conserved site / Proteasome subunit A N-terminal signature / Proteasome alpha-type subunits signature. / Proteasome alpha-subunit, N-terminal domain / Proteasome subunit A N-terminal signature Add an annotation / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome B-type subunit / Proteasome beta-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / Nucleophile aminohydrolases, N-terminal / 4-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-BZ7 / Proteasome subunit alpha type-7 / Proteasome subunit beta type-1 / Proteasome subunit alpha type-1 / Proteasome subunit alpha type-2 / Proteasome subunit alpha type-3 / Proteasome subunit alpha type-4 / Proteasome subunit beta type-8 / Proteasome subunit beta type-9 / Proteasome subunit alpha type-5 ...Chem-BZ7 / Proteasome subunit alpha type-7 / Proteasome subunit beta type-1 / Proteasome subunit alpha type-1 / Proteasome subunit alpha type-2 / Proteasome subunit alpha type-3 / Proteasome subunit alpha type-4 / Proteasome subunit beta type-8 / Proteasome subunit beta type-9 / Proteasome subunit alpha type-5 / Proteasome subunit beta type-4 / Proteasome subunit beta type-10 / Proteasome subunit beta type-3 / Proteasome subunit beta type-2 / Proteasome subunit alpha type-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsLi, H. / Santos, R. / Bai, L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI70285 United States
CitationJournal: 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
DepositionSep 4, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Proteasome subunit beta type-9
B: Proteasome subunit beta type-10
C: Proteasome subunit beta type-8
D: Proteasome subunit beta type-8
E: Proteasome subunit beta type-10
F: Proteasome subunit beta type-9
G: Proteasome subunit alpha type-1
H: Proteasome subunit alpha type-5
I: Proteasome subunit alpha type-7
J: Proteasome subunit alpha type-3
K: Proteasome subunit alpha type-6
L: Proteasome subunit alpha type-1
M: Proteasome subunit alpha type-5
N: Proteasome subunit alpha type-7
O: Proteasome subunit alpha type-4
P: Proteasome subunit alpha type-2
Q: Proteasome subunit alpha type-3
R: Proteasome subunit alpha type-6
S: Proteasome subunit beta type-1
T: Proteasome subunit beta type-2
U: Proteasome subunit beta type-3
V: Proteasome subunit beta type-2
W: Proteasome subunit beta type-4
X: Proteasome subunit beta type-1
Y: Proteasome subunit beta type-3
Z: Proteasome subunit alpha type-4
a: Proteasome subunit beta type-4
b: Proteasome subunit alpha type-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)716,69030
Polymers715,60528
Non-polymers1,0852
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area110300 Å2
ΔGint-413 kcal/mol
Surface area207100 Å2

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Components

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Proteasome subunit beta type- ... , 7 types, 14 molecules AFBECDSXTVUYWa

#1: Protein Proteasome subunit beta type-9 / / Proteasome subunit beta type-6 / Low molecular mass protein 2 / Macropain chain 7 / Multicatalytic ...Proteasome subunit beta type-6 / Low molecular mass protein 2 / Macropain chain 7 / Multicatalytic endopeptidase complex chain 7 / Proteasome chain 7 / Proteasome subunit beta-1i / Really interesting new gene 12 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 Proteasome subunit beta type-10 / / Proteasome subunit beta type-7 / Low molecular mass protein 10 / Macropain subunit MECl-1 / ...Proteasome subunit beta type-7 / Low molecular mass protein 10 / Macropain subunit MECl-1 / Multicatalytic endopeptidase complex subunit MECl-1 / Proteasome MECl-1 / Proteasome subunit beta-2i


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 Proteasome subunit beta type-8 / / Proteasome subunit beta type-5 / Low molecular mass protein 7 / Macropain subunit C13 / ...Proteasome subunit beta type-5 / Low molecular mass protein 7 / Macropain subunit C13 / Multicatalytic endopeptidase complex subunit C13 / Proteasome component C13 / Proteasome subunit beta-5i / Really interesting new gene 10 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 Proteasome subunit beta type-1 / PSMB1 / Macropain subunit C5 / Multicatalytic endopeptidase complex subunit C5 / Proteasome component C5 / ...Macropain subunit C5 / Multicatalytic endopeptidase complex subunit C5 / Proteasome component C5 / Proteasome gamma chain


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 Proteasome subunit beta type-2 / PSMB2 / Macropain subunit C7-I / Multicatalytic endopeptidase complex subunit C7-I / Proteasome component C7-I


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 Proteasome subunit beta type-3 / PSMB3 / Proteasome chain 13 / Proteasome component C10-II / Proteasome theta chain


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 Proteasome subunit beta type-4 / PSMB4 / 26 kDa prosomal protein / PROS-26 / Macropain beta chain / Multicatalytic endopeptidase complex ...26 kDa prosomal protein / PROS-26 / Macropain beta chain / Multicatalytic endopeptidase complex beta chain / Proteasome beta chain / Proteasome chain 3 / HsN3


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 Proteasome subunit alpha type-1 / / 30 kDa prosomal protein / PROS-30 / Macropain subunit C2 / Multicatalytic endopeptidase complex ...30 kDa prosomal protein / PROS-30 / Macropain subunit C2 / Multicatalytic endopeptidase complex subunit C2 / Proteasome component C2 / Proteasome nu chain


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 Proteasome subunit alpha type-5 / / Macropain zeta chain / Multicatalytic endopeptidase complex zeta chain / Proteasome zeta chain


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 Proteasome subunit alpha type-7 / / Proteasome subunit RC6-1 / Proteasome subunit XAPC7


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 Proteasome subunit alpha type-3 / / Macropain subunit C8 / Multicatalytic endopeptidase complex subunit C8 / Proteasome component C8


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 Proteasome subunit alpha type-6 / / 27 kDa prosomal protein / p27K / Macropain iota chain / Multicatalytic endopeptidase complex iota ...27 kDa prosomal protein / p27K / Macropain iota chain / Multicatalytic endopeptidase complex iota chain / Proteasome iota chain


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 Proteasome subunit alpha type-4 / / Macropain subunit C9 / Multicatalytic endopeptidase complex subunit C9 / Proteasome component C9 / ...Macropain subunit C9 / Multicatalytic endopeptidase complex subunit C9 / Proteasome component C9 / Proteasome subunit L


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 Proteasome subunit alpha type-2 / / Macropain subunit C3 / Multicatalytic endopeptidase complex subunit C3 / Proteasome component C3


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 ChemComp-BZ7 / N~1~-{2-[([1,1'-biphenyl]-3-carbonyl)amino]ethyl}-N~4~-tert-butyl-N~2~-(3-phenylpropanoyl)-L-aspartamide / PKS21004


Mass: 542.669 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H38N4O4

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human immunoproteasome with a novel noncompetitive inhibitor that selectively inhibits activated lymphocytes
Type: COMPLEX / Entity ID: #1-#14 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: JEOL 3200FS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.11.1_2575: / Classification: refinement
EM software
IDNameVersionCategory
4CTFFIND4CTF correction
5GctfCTF correction
13RELION1.4classification
14RELION1.43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 75017 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00849104
ELECTRON MICROSCOPYf_angle_d0.84466591
ELECTRON MICROSCOPYf_dihedral_angle_d7.57837450
ELECTRON MICROSCOPYf_chiral_restr0.0487504
ELECTRON MICROSCOPYf_plane_restr0.0058603

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