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- PDB-8ysx: canine immunoproteasome 20S subunit in complex with compound 2 -

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Basic information

Entry
Database: PDB / ID: 8ysx
Titlecanine immunoproteasome 20S subunit in complex with compound 2
Components(Proteasome subunit ...) x 14
KeywordsHYDROLASE / Inhibitor / Complex / Proteasome
Function / homology
Function and homology information


Proteasome assembly / spermatoproteasome complex / proteasome core complex / fat cell differentiation / immune system process / NF-kappaB binding / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / T cell proliferation / threonine-type endopeptidase activity ...Proteasome assembly / spermatoproteasome complex / proteasome core complex / fat cell differentiation / immune system process / NF-kappaB binding / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / T cell proliferation / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / proteolysis involved in protein catabolic process / P-body / nuclear matrix / cell morphogenesis / ubiquitin-dependent protein catabolic process / endopeptidase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / positive regulation of canonical NF-kappaB signal transduction / cilium / ribosome / mitochondrion / RNA binding / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
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 alpha5 / Proteasome subunit alpha6 / 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 alpha5 / Proteasome subunit alpha6 / 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 beta / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta type-8
Similarity search - Component
Biological speciesCanis lupus familiaris (dog)
MethodELECTRON MICROSCOPY / single particle reconstruction / Resolution: 2.2 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 24, 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 / Author supporting evidence / Data collection / Data processing / Database references / Derived calculations / Experimental preparation / Non-polymer description / Polymer sequence / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / em_3d_reconstruction / em_admin / em_ctf_correction / em_software / em_specimen / entity / entity_poly / entity_poly_seq / entity_src_nat / pdbx_entity_instance_feature / pdbx_entity_nonpoly / pdbx_entry_details / pdbx_modification_feature / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly / pdbx_struct_oper_list / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / refine / refine_hist / refine_ls_restr / refine_ls_restr_ncs / refine_ls_shell / struct_conf / struct_conn / struct_ref / struct_ref_seq / struct_sheet_range
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _em_3d_reconstruction.resolution_method / _em_admin.last_update / _em_ctf_correction.em_image_processing_id / _em_specimen.vitrification_applied / _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.auth_mon_id / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_nonpoly_scheme.pdb_seq_num / _pdbx_struct_assembly.details / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_unobs_or_zero_occ_residues.label_seq_id / _refine.B_iso_mean / _refine.aniso_B[1][1] / _refine.aniso_B[1][2] / _refine.aniso_B[1][3] / _refine.aniso_B[2][2] / _refine.aniso_B[2][3] / _refine.aniso_B[3][3] / _refine.correlation_coeff_Fo_to_Fc / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.ls_d_res_low / _refine.ls_number_reflns_obs / _refine.ls_percent_reflns_obs / _refine.overall_SU_B / _refine.overall_SU_ML / _refine.pdbx_overall_ESU_R / _refine.pdbx_stereochemistry_target_values / _refine.solvent_model_details / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id
Revision 2.1Oct 23, 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
F: Proteasome subunit beta
L: Proteasome subunit alpha type
M: Proteasome subunit alpha type
N: Proteasome subunit alpha type
O: Proteasome subunit alpha type
R: Proteasome subunit alpha type
T: Proteasome subunit beta
U: Proteasome subunit beta
a: Proteasome subunit beta
C: Proteasome subunit beta type-8
b: Proteasome subunit alpha type
X: Proteasome subunit beta
H: Proteasome subunit alpha type
I: Proteasome subunit alpha type
J: Proteasome subunit alpha type
V: Proteasome subunit beta
Y: Proteasome subunit beta
Z: Proteasome subunit alpha type
G: Proteasome subunit alpha type
E: Proteasome subunit beta
W: Proteasome subunit beta
B: Proteasome subunit beta
Q: Proteasome subunit alpha type
A: Proteasome subunit beta
K: Proteasome subunit alpha type
D: Proteasome subunit beta type-8
P: Proteasome subunit alpha type
S: Proteasome subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)732,35832
Polymers731,02128
Non-polymers1,3374
Water28816
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#1: 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: A0A8C0T7K4
#2: 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
#3: 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
#4: 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
#5: 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
#6: 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
#7: 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
#8: 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
#9: 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
#10: 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
#11: 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
#12: 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
#13: 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
#14: Protein Proteasome subunit beta


Mass: 24884.293 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Canis lupus familiaris (dog) / References: UniProt: A0A8C0SLB3

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Non-polymers , 2 types, 20 molecules

#15: Chemical
ChemComp-A1L0D / [(~{R})-cyclohexyl-[(1-cyclohexyl-1,2,3-triazol-4-yl)carbonylamino]methyl]boronic acid


Mass: 334.222 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H27BN4O3
#16: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / Source method: isolated from a natural source / Formula: H2O

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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: #1-#9, #11-#14 / Source: NATURAL
Source (natural)Organism: Canis lupus familiaris (dog)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: NO
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: 56.7 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: REFMAC
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.2 Å / Num. of particles: 304965 / Symmetry type: POINT
RefinementHighest resolution: 2.2 Å

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