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- PDB-4eu2: Crystal structure of 20s proteasome with novel inhibitor K-7174 -

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Basic information

Entry
Database: PDB / ID: 4eu2
TitleCrystal structure of 20s proteasome with novel inhibitor K-7174
Components(Proteasome component ...) x 14
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Proteasome inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


proteasome core complex assembly / nuclear outer membrane-endoplasmic reticulum membrane network / Cross-presentation of soluble exogenous antigens (endosomes) / TNFR2 non-canonical NF-kB pathway / proteasomal ubiquitin-independent protein catabolic process / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Regulation of PTEN stability and activity / CDK-mediated phosphorylation and removal of Cdc6 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / KEAP1-NFE2L2 pathway ...proteasome core complex assembly / nuclear outer membrane-endoplasmic reticulum membrane network / Cross-presentation of soluble exogenous antigens (endosomes) / TNFR2 non-canonical NF-kB pathway / proteasomal ubiquitin-independent protein catabolic process / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Regulation of PTEN stability and activity / CDK-mediated phosphorylation and removal of Cdc6 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / KEAP1-NFE2L2 pathway / Neddylation / Orc1 removal from chromatin / MAPK6/MAPK4 signaling / proteasome storage granule / Antigen processing: Ubiquitination & Proteasome degradation / endopeptidase activator activity / proteasome assembly / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / Ub-specific processing proteases / threonine-type endopeptidase activity / Neutrophil degranulation / proteasome complex / peroxisome / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / mRNA binding / endoplasmic reticulum membrane / mitochondrion / nucleus / cytosol
Similarity search - Function
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. ...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-WPI / Probable proteasome subunit alpha type-7 / Proteasome subunit alpha type-1 / Proteasome subunit beta type-4 / Proteasome subunit alpha type-3 / Proteasome subunit alpha type-2 / Proteasome subunit beta type-6 / Proteasome subunit beta type-2 / Proteasome subunit beta type-3 / Proteasome subunit beta type-5 ...Chem-WPI / Probable proteasome subunit alpha type-7 / Proteasome subunit alpha type-1 / Proteasome subunit beta type-4 / Proteasome subunit alpha type-3 / Proteasome subunit alpha type-2 / Proteasome subunit beta type-6 / Proteasome subunit beta type-2 / Proteasome subunit beta type-3 / Proteasome subunit beta type-5 / Proteasome subunit beta type-7 / Proteasome subunit alpha type-5 / Proteasome subunit beta type-1 / Proteasome subunit alpha type-6 / Proteasome subunit alpha type-4
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.509 Å
AuthorsKikuchi, J. / Shibayama, N. / Yamada, S. / Wada, T. / Nobuyoshi, M. / Izumi, T. / Akutsu, M. / Kano, Y. / Ohki, M. / Sugiyama, K. ...Kikuchi, J. / Shibayama, N. / Yamada, S. / Wada, T. / Nobuyoshi, M. / Izumi, T. / Akutsu, M. / Kano, Y. / Ohki, M. / Sugiyama, K. / Park, S.-Y. / Furukawa, Y.
CitationJournal: Plos One / Year: 2013
Title: Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.
Authors: Kikuchi, J. / Shibayama, N. / Yamada, S. / Wada, T. / Nobuyoshi, M. / Izumi, T. / Akutsu, M. / Kano, Y. / Sugiyama, K. / Ohki, M. / Park, S.Y. / Furukawa, Y.
History
DepositionApr 25, 2012Deposition site: RCSB / Processing site: PDBJ
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Proteasome component C7-alpha
B: Proteasome component Y7
C: Proteasome component Y13
D: Proteasome component PRE6
E: Proteasome component PUP2
F: Proteasome component PRE5
G: Proteasome component C1
H: Proteasome component PRE3
I: Proteasome component PUP1
J: Proteasome component PUP3
K: Proteasome component C11
L: Proteasome component PRE2
M: Proteasome component C5
N: Proteasome component PRE4
O: Proteasome component C7-alpha
P: Proteasome component Y7
Q: Proteasome component Y13
R: Proteasome component PRE6
S: Proteasome component PUP2
T: Proteasome component PRE5
U: Proteasome component C1
V: Proteasome component PRE3
W: Proteasome component PUP1
X: Proteasome component PUP3
Y: Proteasome component C11
Z: Proteasome component PRE2
1: Proteasome component C5
2: Proteasome component PRE4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)707,18834
Polymers703,77628
Non-polymers3,4126
Water18,1771009
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area120330 Å2
ΔGint-337 kcal/mol
Surface area214130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)134.264, 301.363, 143.964
Angle α, β, γ (deg.)90.000, 112.860, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Proteasome component ... , 14 types, 28 molecules AOBPCQDRESFTGUHVIWJXKYLZM1N2

#1: Protein Proteasome component C7-alpha / Macropain subunit C7-alpha / Multicatalytic endopeptidase complex C7 / Proteasome component Y8 / ...Macropain subunit C7-alpha / Multicatalytic endopeptidase complex C7 / Proteasome component Y8 / Proteinase YSCE subunit 7 / SCL1 suppressor protein


Mass: 27072.818 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 10-250 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P21243, proteasome endopeptidase complex
#2: Protein Proteasome component Y7 / Macropain subunit Y7 / Multicatalytic endopeptidase complex subunit Y7 / Proteinase YSCE subunit 7


Mass: 27191.828 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P23639, proteasome endopeptidase complex
#3: Protein Proteasome component Y13 / Macropain subunit Y13 / Multicatalytic endopeptidase complex subunit Y13 / Proteinase YSCE subunit 13


Mass: 27050.416 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 2-245 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P23638, proteasome endopeptidase complex
#4: Protein Proteasome component PRE6 / Macropain subunit PRE6 / Multicatalytic endopeptidase complex subunit PRE6 / Proteinase YSCE subunit PRE6


Mass: 26903.330 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 3-243 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P40303, proteasome endopeptidase complex
#5: Protein Proteasome component PUP2 / Macropain subunit PUP2 / Multicatalytic endopeptidase complex subunit PUP2 / Proteinase YSCE subunit PUP2


Mass: 26544.789 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 9-250 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P32379, proteasome endopeptidase complex
#6: Protein Proteasome component PRE5 / Macropain subunit PRE5 / Multicatalytic endopeptidase complex subunit PRE5 / Proteinase YSCE subunit PRE5


Mass: 25502.805 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P40302, proteasome endopeptidase complex
#7: Protein Proteasome component C1 / Macropain subunit C1 / Multicatalytic endopeptidase complex subunit C1 / Proteinase YSCE subunit 1


Mass: 26892.482 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 5-248 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P21242, proteasome endopeptidase complex
#8: Protein Proteasome component PRE3 / Macropain subunit PRE3 / Multicatalytic endopeptidase complex subunit PRE3 / Proteinase YSCE subunit PRE3


Mass: 21517.186 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P38624, proteasome endopeptidase complex
#9: Protein Proteasome component PUP1 / Macropain subunit PUP1 / Multicatalytic endopeptidase complex subunit PUP1 / Proteinase YSCE subunit PUP1


Mass: 23987.254 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P25043, proteasome endopeptidase complex
#10: Protein Proteasome component PUP3 / Macropain subunit PUP3 / Multicatalytic endopeptidase complex subunit PUP3


Mass: 22496.645 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P25451, proteasome endopeptidase complex
#11: Protein Proteasome component C11 / Macropain subunit C11 / Multicatalytic endopeptidase complex subunit C11 / Proteinase YSCE subunit 11


Mass: 22545.676 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P22141, proteasome endopeptidase complex
#12: Protein Proteasome component PRE2 / Macropain subunit PRE2 / Multicatalytic endopeptidase complex subunit PRE2 / Proteinase YSCE subunit PRE2


Mass: 23353.262 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P30656, proteasome endopeptidase complex
#13: Protein Proteasome component C5 / Multicatalytic endopeptidase complex subunit C5


Mass: 24883.928 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P23724, proteasome endopeptidase complex
#14: Protein Proteasome component PRE4 / Macropain subunit PRE4 / Multicatalytic endopeptidase complex subunit PRE4 / Proteinase YSCE subunit PRE4


Mass: 25945.496 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / Strain: S288c
References: UniProt: P30657, proteasome endopeptidase complex

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Non-polymers , 2 types, 1015 molecules

#15: Chemical
ChemComp-WPI / 1,4-bis[(4E)-5-(3,4,5-trimethoxyphenyl)pent-4-en-1-yl]-1,4-diazepane


Mass: 568.744 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C33H48N2O6
#16: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1009 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.81 Å3/Da / Density % sol: 67.75 % / Mosaicity: 0.496 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 4.5% (v/v) 2-methyl1-2,4-pentanediol(MPD), 36mM magnesium acetate, 90mM MES pH7.2, 10%(v/v) DMSO, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: MAR225HE / Detector: CCD / Date: Nov 17, 2011 / Details: Si111
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 313772 / % possible obs: 88.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.3 % / Rmerge(I) obs: 0.101 / Χ2: 2.826 / Net I/σ(I): 12.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.5-2.541.90.28127880.856172.3
2.54-2.5920.273134210.877176.1
2.59-2.642.10.261138270.911177.9
2.64-2.692.10.25141731.003180
2.69-2.752.30.237143240.97181.2
2.75-2.822.40.243146011.212182.4
2.82-2.892.50.207147881.09183.5
2.89-2.962.60.197150371.121185
2.96-3.052.70.181152701.26186.3
3.05-3.152.90.162156621.396188.3
3.15-3.263.10.144160261.52190.5
3.26-3.393.40.127162801.676191.8
3.39-3.553.60.11166331.954194
3.55-3.733.80.103168762.163195.2
3.73-3.9740.088169362.376195.4
3.97-4.274.20.086171333.14196.6
4.27-4.74.40.098172845.712197.4
4.7-5.384.50.106174246.962198.1
5.38-6.784.40.077175523.391198.5
6.78-504.80.044177373.517198.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PHENIX1.7.3_928refinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.509→45.701 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8153 / SU ML: 0.35 / σ(F): 0 / σ(I): 0 / Phase error: 26.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2547 15839 5.05 %RANDOM
Rwork0.2019 ---
all0.2046 ---
obs0.2046 313700 87.6 %-
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 14.453 Å2 / ksol: 0.288 e/Å3
Displacement parametersBiso max: 142.22 Å2 / Biso mean: 38.8345 Å2 / Biso min: 10.36 Å2
Baniso -1Baniso -2Baniso -3
1-12.3445 Å2-0 Å2-4.2365 Å2
2---16.6043 Å2-0 Å2
3---4.2597 Å2
Refinement stepCycle: LAST / Resolution: 2.509→45.701 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms49446 0 246 1009 50701
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00850577
X-RAY DIFFRACTIONf_angle_d1.17868385
X-RAY DIFFRACTIONf_chiral_restr0.0787663
X-RAY DIFFRACTIONf_plane_restr0.0058805
X-RAY DIFFRACTIONf_dihedral_angle_d17.28718664
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5089-2.53740.3683010.32066021632253
2.5374-2.56730.40464430.34338317876073
2.5673-2.59860.37684610.32818489895075
2.5986-2.63150.37674690.32358710917977
2.6315-2.66610.35594430.30438930937378
2.6661-2.70260.32934820.30749012949480
2.7026-2.74120.35394680.29349170963881
2.7412-2.78210.32294960.28259188968482
2.7821-2.82560.33444900.2699333982383
2.8256-2.87190.32634950.26339413990883
2.8719-2.92140.31194900.24319508999884
2.9214-2.97460.30175420.243695691011185
2.9746-3.03180.30675230.238296991022286
3.0318-3.09360.27495230.229298341035787
3.0936-3.16090.27745410.228599481048988
3.1609-3.23440.28375440.2154102201076490
3.2344-3.31520.26485070.2021103181082591
3.3152-3.40490.25475470.1911104341098192
3.4049-3.5050.25085450.1803105941113993
3.505-3.61810.23145470.1714107051125294
3.6181-3.74740.23946060.1712107971140396
3.7474-3.89730.2256180.1613107411135995
3.8973-4.07460.26200.1587108531147396
4.0746-4.28930.20515760.1499109491152597
4.2893-4.55780.19945800.1413110541163497
4.5578-4.90930.1945670.1434111211168898
4.9093-5.40260.22036000.1676111561175698
5.4026-6.18280.26915920.1981111781177098
6.1828-7.78340.21166000.167112491184999
7.7834-45.7090.17996230.1637113511197499

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