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- PDB-8yvg: canine immunoproteasome 20S subunit in complex with compound 1 -

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Basic information

Entry
Database: PDB / ID: 8yvg
Titlecanine immunoproteasome 20S subunit in complex with compound 1
Components(Proteasome subunit ...) x 14
KeywordsHYDROLASE / Inhibitor / Complex / Immunoproteasome
Function / homology
Function and homology information


Proteasome assembly / spermatoproteasome complex / proteasome core complex / fat cell differentiation / immune system process / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process ...Proteasome assembly / spermatoproteasome complex / proteasome core complex / fat cell differentiation / immune system process / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / T cell proliferation / proteolysis involved in protein catabolic process / P-body / cell morphogenesis / response to virus / ubiquitin-dependent protein catabolic process / endopeptidase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Proteasome subunit alpha 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 subunit alpha 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 B-type subunit / Proteasome beta-type subunit profile. / : / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / Nucleophile aminohydrolases, N-terminal
Similarity search - Domain/homology
: / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit alpha type ...: / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit beta type-8
Similarity search - Component
Biological speciesCanis lupus familiaris (dog)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2 Å
AuthorsKashima, A. / Arai, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: 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
DepositionMar 28, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 2.0Oct 9, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / em_admin / entity / entity_poly / entity_poly_seq / entity_src_nat / pdbx_entity_nonpoly / pdbx_entry_details / pdbx_modification_feature / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / pdbx_validate_close_contact / pdbx_validate_torsion / struct_conf / struct_conn / struct_ref / struct_ref_seq / struct_sheet_range
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.group_PDB / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.label_seq_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _em_admin.last_update / _entity.formula_weight / _entity.pdbx_description / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_nat.pdbx_end_seq_num / _pdbx_entity_nonpoly.name / _pdbx_entry_details.has_protein_modification / _pdbx_nonpoly_scheme.pdb_seq_num / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_unobs_or_zero_occ_residues.auth_seq_id / _pdbx_unobs_or_zero_occ_residues.label_seq_id / _pdbx_validate_torsion.auth_seq_id / _struct_conf.beg_auth_seq_id / _struct_conf.beg_label_seq_id / _struct_conf.end_auth_seq_id / _struct_conf.end_label_seq_id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_ref.db_code / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_auth_seq_id / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_auth_seq_id / _struct_sheet_range.end_label_seq_id
Revision 2.1Oct 16, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)741,12032
Polymers739,88728
Non-polymers1,2334
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
22
33
44
55
66
77
88
99
1010
1111
1212
1313
1414
/ NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14

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Components

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Proteasome subunit ... , 14 types, 28 molecules MHNIOZPbQJTVUYCDSXGLKRFAEBWa

#1: Protein Proteasome subunit alpha type


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 Proteasome subunit alpha type


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 Proteasome subunit alpha type


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 Proteasome subunit alpha type


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 Proteasome subunit alpha type


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 Proteasome subunit beta


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 Proteasome subunit beta


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 Proteasome subunit beta type-8 / Proteasome subunit beta-5i


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 Proteasome subunit beta


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 Proteasome subunit alpha type


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 Proteasome subunit alpha type


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 Proteasome subunit beta


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 Proteasome subunit beta


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 Proteasome subunit beta


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 / [(1R)-1-[(1-cyclohexyl-1,2,3-triazol-4-yl)carbonylamino]-3-methyl-butyl]boronic acid


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 interestY
Has protein modificationY

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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: 20S immunoproteasome / Type: COMPLEX / Entity ID: #10, #1-#5, #11, #6-#7, #14, #9, #13 / Source: NATURAL
Source (natural)Organism: Canis lupus familiaris (dog)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 91.875 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: REFMAC / Version: 5.8.0258 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 896501 / Symmetry type: POINT
RefinementResolution: 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
RfactorNum. reflection% reflection
Rwork0.29883 --
obs0.29883 801996 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 44.183 Å2
Baniso -1Baniso -2Baniso -3
1--0.2 Å20.02 Å20 Å2
2---0.07 Å2-0 Å2
3---0.27 Å2
Refinement stepCycle: 1 / Total: 47948
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0130.01248830
ELECTRON MICROSCOPYr_bond_other_d
ELECTRON MICROSCOPYr_angle_refined_deg2.0281.63566016
ELECTRON MICROSCOPYr_angle_other_deg
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.80156136
ELECTRON MICROSCOPYr_dihedral_angle_2_deg35.22922.0162490
ELECTRON MICROSCOPYr_dihedral_angle_3_deg19.448158474
ELECTRON MICROSCOPYr_dihedral_angle_4_deg19.79615330
ELECTRON MICROSCOPYr_chiral_restr0.1370.26398
ELECTRON MICROSCOPYr_gen_planes_refined0.0120.0236998
ELECTRON MICROSCOPYr_gen_planes_other
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it7.4363.50724634
ELECTRON MICROSCOPYr_mcbond_other
ELECTRON MICROSCOPYr_mcangle_it10.2635.27130740
ELECTRON MICROSCOPYr_mcangle_other
ELECTRON MICROSCOPYr_scbond_it12.5084.99424196
ELECTRON MICROSCOPYr_scbond_other
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other
ELECTRON MICROSCOPYr_long_range_B_refined22.14771.323198947
ELECTRON MICROSCOPYr_long_range_B_other
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: ELECTRON MICROSCOPY / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11F129520
12A129520
21L153920
22G153920
31M143900
32H143900
41N147700
42I147700
51O156020
52Z156020
61P148500
62b148500
71Q155100
72J155100
81R151360
82K151360
91T131220
92V131220
101U133300.01
102Y133300.01
111a140360
112W140360
121C138500
122D138500
131B133180
132E133180
141X137420
142S137420
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.642 59255 -
obs--100 %

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