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- PDB-2gpl: TMC-95 based biphenyl-ether macrocycles: specific proteasome inhi... -

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Basic information

Entry
Database: PDB / ID: 2gpl
TitleTMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors
Components(Proteasome component ...) x 14
KeywordsHYDROLASE / Proteasomal subunit fold represents an antiparallel beta-sheet flanked by helices / Ntn-Hydrolase
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-BIQ / 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-BIQ / 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 / FOURIER SYNTHESIS / Resolution: 2.81 Å
AuthorsGroll, M. / Goetz, M. / Kaiser, M. / Weyher, E. / Moroder, M.
CitationJournal: Chem.Biol. / Year: 2006
Title: TMC-95-Based Inhibitor Design Provides Evidence for the Catalytic Versatility of the Proteasome.
Authors: Groll, M. / Goetz, M. / Kaiser, M. / Weyher, E. / Moroder, L.
History
DepositionApr 18, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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 Y7
B: Proteasome component Y13
C: Proteasome component PRE6
D: Proteasome component PUP2
E: Proteasome component PRE5
F: Proteasome component C1
G: Proteasome component C7-alpha
H: Proteasome component PUP1
I: Proteasome component PUP3
J: Proteasome component C11
K: Proteasome component PRE2
L: Proteasome component C5
M: Proteasome component PRE4
N: Proteasome component PRE3
O: Proteasome component Y7
P: Proteasome component Y13
Q: Proteasome component PRE6
R: Proteasome component PUP2
S: Proteasome component PRE5
T: Proteasome component C1
U: Proteasome component C7-alpha
V: Proteasome component PUP1
W: Proteasome component PUP3
X: Proteasome component C11
Y: Proteasome component PRE2
Z: Proteasome component C5
1: Proteasome component PRE4
2: Proteasome component PRE3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)705,52830
Polymers704,20628
Non-polymers1,3212
Water19,2761070
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area117910 Å2
ΔGint-350 kcal/mol
Surface area214550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)136.425, 300.962, 144.762
Angle α, β, γ (deg.)90.00, 113.17, 90.00
Int Tables number4
Space group name H-MP1211
DetailsThe biological assembly is the whole content of the asymmetric unit cell.

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Components

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

#1: Protein Proteasome component Y7 / Macropain subunit Y7 / Proteinase YSCE subunit 7 / Multicatalytic endopeptidase complex subunit Y7


Mass: 27191.828 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRS4, PRE8 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P23639, proteasome endopeptidase complex
#2: Protein Proteasome component Y13 / Macropain subunit Y13 / Proteinase YSCE subunit 13 / Multicatalytic endopeptidase complex subunit Y13


Mass: 27050.416 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRS5, PRE9 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P23638, proteasome endopeptidase complex
#3: Protein Proteasome component PRE6 / Macropain subunit PRE6 / Proteinase YSCE subunit PRE6 / Multicatalytic endopeptidase complex subunit PRE6


Mass: 26903.330 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRE6 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P40303, proteasome endopeptidase complex
#4: Protein Proteasome component PUP2 / Macropain subunit PUP2 / Proteinase YSCE subunit PUP2 / Multicatalytic endopeptidase complex subunit PUP2


Mass: 26544.789 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PUP2, DOA5 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P32379, proteasome endopeptidase complex
#5: Protein Proteasome component PRE5 / Macropain subunit PRE5 / Proteinase YSCE subunit PRE5 / Multicatalytic endopeptidase complex subunit PRE5


Mass: 25502.805 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRE5 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P40302, proteasome endopeptidase complex
#6: Protein Proteasome component C1 / Macropain subunit C1 / Proteinase YSCE subunit 1 / Multicatalytic endopeptidase complex subunit C1


Mass: 26892.482 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRS1, PRC1, PRE10 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P21242, proteasome endopeptidase complex
#7: Protein Proteasome component C7-alpha / Macropain subunit C7- alpha / Proteinase YSCE subunit 7 / Multicatalytic endopeptidase complex C7 / ...Macropain subunit C7- alpha / Proteinase YSCE subunit 7 / Multicatalytic endopeptidase complex C7 / Component Y8 / SCL1 suppressor protein


Mass: 27316.037 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRS2, PRC2, SCL1 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P21243, proteasome endopeptidase complex
#8: Protein Proteasome component PUP1 / Macropain subunit PUP1 / Proteinase YSCE subunit PUP1 / Multicatalytic endopeptidase complex subunit PUP1


Mass: 23987.254 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PUP1 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P25043, proteasome endopeptidase complex
#9: 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 genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PUP3 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P25451, proteasome endopeptidase complex
#10: Protein Proteasome component C11 / Macropain subunit C11 / Proteinase YSCE subunit 11 / Multicatalytic endopeptidase complex subunit C11


Mass: 22545.676 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRE1 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P22141, proteasome endopeptidase complex
#11: Protein Proteasome component PRE2 / Macropain subunit PRE2 / Proteinase YSCE subunit PRE2 / Multicatalytic endopeptidase complex subunit PRE2


Mass: 23325.248 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRE2, DOA3, PRG1 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P30656, proteasome endopeptidase complex
#12: Protein Proteasome component C5 / Multicatalytic endopeptidase complex subunit C5


Mass: 24883.928 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRS3, PRE7, PTS1 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P23724, proteasome endopeptidase complex
#13: Protein Proteasome component PRE4 / Macropain subunit PRE4 / Proteinase YSCE subunit PRE4 / Multicatalytic endopeptidase complex subunit PRE4


Mass: 25945.496 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRE4 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P30657, proteasome endopeptidase complex
#14: Protein Proteasome component PRE3 / Macropain subunit PRE3 / Proteinase YSCE subunit PRE3 / Multicatalytic endopeptidase complex subunit PRE3


Mass: 21517.186 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: PRE3 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P38624, proteasome endopeptidase complex

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Non-polymers , 2 types, 1072 molecules

#15: Chemical ChemComp-BIQ / BENZYL [12-(2-AMINO-2-OXOETHYL)-4-NITRO-10,13-DIOXO-15-[(PROPYLAMINO)CARBONYL]-2-OXA-11,14-DIAZATRICYCLO[15 .2.2.1~3,7~]DOCOSA-1(19),3(22),4,6,17,20-HEXAEN-9-YL]CARBAMATE


Mass: 660.674 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H36N6O9
#16: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1070 / 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: 3.88 Å3/Da / Density % sol: 68.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.7
Details: 20mM MgAc2; 0.1M MES, 12% MPD; crystals appeared within 7 days; crystal size 0.2 x 0.2 x 0.6 mm3, pH 6.7, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MPG/DESY, HAMBURG / Beamline: BW6 / Wavelength: 1.05 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jun 30, 2005
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.05 Å / Relative weight: 1
ReflectionResolution: 2.8→15 Å / Num. all: 255964 / Num. obs: 252489 / % possible obs: 97.6 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 41.9 Å2 / Rmerge(I) obs: 0.062
Reflection shellResolution: 2.81→2.85 Å / Rmerge(I) obs: 0.331 / % possible all: 85.8

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Processing

Software
NameVersionClassification
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
CNS1.1phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: yeast 20S proteasome (1RYP)

1ryp


Resolution: 2.81→15 Å / Rfactor Rfree error: 0.002 / Data cutoff high absF: 3454667.77 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.241 12489 5 %RANDOM
Rwork0.217 ---
all0.282 251453 --
obs0.217 250974 97.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 37.0575 Å2 / ksol: 0.32717 e/Å3
Displacement parametersBiso mean: 53.2 Å2
Baniso -1Baniso -2Baniso -3
1-11.33 Å20 Å2-0.96 Å2
2---23.55 Å20 Å2
3---12.22 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.41 Å0.37 Å
Luzzati d res low-5 Å
Luzzati sigma a0.5 Å0.45 Å
Refinement stepCycle: LAST / Resolution: 2.81→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms49548 0 96 1070 50714
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_improper_angle_d0.77
LS refinement shellResolution: 2.8→2.97 Å / Rfactor Rfree error: 0.008 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.362 1874 5 %
Rwork0.327 35777 -
obs--86.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.parambia.top
X-RAY DIFFRACTION3ion.param
X-RAY DIFFRACTION4bia.par

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