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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


Activation of NF-kappaB in B cells / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Cross-presentation of soluble exogenous antigens (endosomes) / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SCF(Skp2)-mediated degradation of p27/p21 / Degradation of beta-catenin by the destruction complex / Downstream TCR signaling ...Activation of NF-kappaB in B cells / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Cross-presentation of soluble exogenous antigens (endosomes) / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SCF(Skp2)-mediated degradation of p27/p21 / Degradation of beta-catenin by the destruction complex / Downstream TCR signaling / Separation of Sister Chromatids / FCERI mediated NF-kB activation / Autodegradation of the E3 ubiquitin ligase COP1 / Regulation of ornithine decarboxylase (ODC) / ABC-family proteins mediated transport / AUF1 (hnRNP D0) binds and destabilizes mRNA / Asymmetric localization of PCP proteins / Degradation of AXIN / Degradation of DVL / Hedgehog ligand biogenesis / Dectin-1 mediated noncanonical NF-kB signaling / CLEC7A (Dectin-1) signaling / Degradation of GLI1 by the proteasome / GLI3 is processed to GLI3R by the proteasome / Hedgehog 'on' state / Regulation of RAS by GAPs / NIK-->noncanonical NF-kB signaling / UCH proteinases / Ub-specific processing proteases / Assembly of the pre-replicative complex / Orc1 removal from chromatin / CDK-mediated phosphorylation and removal of Cdc6 / G2/M Checkpoints / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Ubiquitin-dependent degradation of Cyclin D / The role of GTSE1 in G2/M progression after G2 checkpoint / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Regulation of RUNX2 expression and activity / Regulation of RUNX3 expression and activity / Regulation of PTEN stability and activity / Neddylation / Interleukin-1 signaling / KEAP1-NFE2L2 pathway / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Antigen processing: Ubiquitination & Proteasome degradation / TNFR2 non-canonical NF-kB pathway / MAPK6/MAPK4 signaling / spermatoproteasome complex / proteasome core complex / immune system process / fat cell differentiation / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / threonine-type endopeptidase activity / T cell proliferation / proteolysis involved in protein catabolic process / P-body / response to virus / cell morphogenesis / ubiquitin-dependent protein catabolic process / postsynapse / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / 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 alpha6 / Proteasome subunit alpha5 / Proteasome beta-type subunits signature. ...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 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
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 / cryo EM / 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

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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)732,37432
Polymers730,61728
Non-polymers1,7574
Water28816
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 FALGMHNIOZRKTVUYaWCDbPXSJQEB

#1: Protein Proteasome subunit beta


Mass: 21134.789 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: 22629.408 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 / [(2~{R},3~{R})-3-azanyl-4-oxidanyl-butan-2-yl]oxy-[(~{R})-cyclohexyl-[(1-cyclohexyl-1,2,3-triazol-4-yl)carbonylamino]methyl]-$l^{3}-oxidanyl-oxidanyl-boron


Mass: 439.357 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H38BN5O5 / Feature type: SUBJECT OF INVESTIGATION
#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

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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: 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: 56.7 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: REFMAC / Version: 5.8.0257 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 304965 / Symmetry type: POINT
RefinementResolution: 2.2→2.2 Å / Cor.coef. Fo:Fc: 0.789 / SU B: 7.471 / SU ML: 0.162 / ESU R: 0.263
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
RfactorNum. reflection% reflection
Rwork0.3041 --
obs0.3041 532172 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 47.642 Å2
Baniso -1Baniso -2Baniso -3
1-0.21 Å2-0.92 Å20 Å2
2---0.21 Å2-0 Å2
3---0.01 Å2
Refinement stepCycle: 1 / Total: 47972
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0120.01248838
ELECTRON MICROSCOPYr_bond_other_d
ELECTRON MICROSCOPYr_angle_refined_deg1.9381.63666020
ELECTRON MICROSCOPYr_angle_other_deg
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.58756132
ELECTRON MICROSCOPYr_dihedral_angle_2_deg35.8922.0162490
ELECTRON MICROSCOPYr_dihedral_angle_3_deg18.715158474
ELECTRON MICROSCOPYr_dihedral_angle_4_deg20.53415330
ELECTRON MICROSCOPYr_chiral_restr0.1270.26406
ELECTRON MICROSCOPYr_gen_planes_refined0.0110.0236998
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_it6.4774.01824626
ELECTRON MICROSCOPYr_mcbond_other
ELECTRON MICROSCOPYr_mcangle_it9.0976.03830724
ELECTRON MICROSCOPYr_mcangle_other
ELECTRON MICROSCOPYr_scbond_it10.5845.22724212
ELECTRON MICROSCOPYr_scbond_other
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other
ELECTRON MICROSCOPYr_long_range_B_refined19.08479.918200967
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 / Rms dev position: 0 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11E13590
12B13590
21F12812
22A12812
31L15432
32G15432
41M14438
42H14438
51N14768
52I14768
61O15494
62Z15494
71P14862
72b14862
81Q15754
82J15754
91R15228
92K15228
101T13146
102V13146
111U13500
112Y13500
121a14134
122W14134
131C13680
132D13680
141X13856
142S13856
LS refinement shellResolution: 2.2→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.615 39576 -
obs--100 %

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