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- PDB-7uvu: Crystal structure of human ClpP protease in complex with TR-107 -

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Basic information

Entry
Database: PDB / ID: 7uvu
TitleCrystal structure of human ClpP protease in complex with TR-107
ComponentsATP-dependent Clp protease proteolytic subunit, mitochondrial
KeywordsHYDROLASE/AGONIST / agonist / protease / degradation / apoptosis / cancer / HYDROLASE / HYDROLASE-AGONIST complex
Function / homology
Function and homology information


membrane protein proteolysis / mitochondrial protein catabolic process / endopeptidase Clp / endopeptidase Clp complex / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / Mitochondrial protein degradation / proteolysis involved in protein catabolic process / peptidase activity / ATPase binding ...membrane protein proteolysis / mitochondrial protein catabolic process / endopeptidase Clp / endopeptidase Clp complex / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / Mitochondrial protein degradation / proteolysis involved in protein catabolic process / peptidase activity / ATPase binding / endopeptidase activity / mitochondrial matrix / serine-type endopeptidase activity / mitochondrion / proteolysis / identical protein binding
Similarity search - Function
ClpP, Ser active site / Endopeptidase Clp serine active site. / ClpP, histidine active site / Endopeptidase Clp histidine active site. / ATP-dependent Clp protease proteolytic subunit / Clp protease proteolytic subunit /Translocation-enhancing protein TepA / Clp protease / ClpP/crotonase-like domain superfamily
Similarity search - Domain/homology
Chem-OY9 / ATP-dependent Clp protease proteolytic subunit, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.24 Å
AuthorsMabanglo, M.F. / Houry, W.A.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT-173345 Canada
CitationJournal: Structure / Year: 2023
Title: Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome.
Authors: Mabanglo, M.F. / Wong, K.S. / Barghash, M.M. / Leung, E. / Chuang, S.H.W. / Ardalan, A. / Majaesic, E.M. / Wong, C.J. / Zhang, S. / Lang, H. / Karanewsky, D.S. / Iwanowicz, A.A. / Graves, L. ...Authors: Mabanglo, M.F. / Wong, K.S. / Barghash, M.M. / Leung, E. / Chuang, S.H.W. / Ardalan, A. / Majaesic, E.M. / Wong, C.J. / Zhang, S. / Lang, H. / Karanewsky, D.S. / Iwanowicz, A.A. / Graves, L.M. / Iwanowicz, E.J. / Gingras, A.C. / Houry, W.A.
History
DepositionMay 2, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 15, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-dependent Clp protease proteolytic subunit, mitochondrial
B: ATP-dependent Clp protease proteolytic subunit, mitochondrial
C: ATP-dependent Clp protease proteolytic subunit, mitochondrial
D: ATP-dependent Clp protease proteolytic subunit, mitochondrial
E: ATP-dependent Clp protease proteolytic subunit, mitochondrial
F: ATP-dependent Clp protease proteolytic subunit, mitochondrial
G: ATP-dependent Clp protease proteolytic subunit, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,99514
Polymers169,2597
Non-polymers2,7367
Water2,252125
1
A: ATP-dependent Clp protease proteolytic subunit, mitochondrial
B: ATP-dependent Clp protease proteolytic subunit, mitochondrial
C: ATP-dependent Clp protease proteolytic subunit, mitochondrial
D: ATP-dependent Clp protease proteolytic subunit, mitochondrial
E: ATP-dependent Clp protease proteolytic subunit, mitochondrial
F: ATP-dependent Clp protease proteolytic subunit, mitochondrial
G: ATP-dependent Clp protease proteolytic subunit, mitochondrial
hetero molecules

A: ATP-dependent Clp protease proteolytic subunit, mitochondrial
B: ATP-dependent Clp protease proteolytic subunit, mitochondrial
C: ATP-dependent Clp protease proteolytic subunit, mitochondrial
D: ATP-dependent Clp protease proteolytic subunit, mitochondrial
E: ATP-dependent Clp protease proteolytic subunit, mitochondrial
F: ATP-dependent Clp protease proteolytic subunit, mitochondrial
G: ATP-dependent Clp protease proteolytic subunit, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)343,99028
Polymers338,51814
Non-polymers5,47214
Water25214
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area53880 Å2
ΔGint-271 kcal/mol
Surface area84070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.147, 152.662, 104.342
Angle α, β, γ (deg.)90.000, 118.010, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11F-410-

HOH

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Components

#1: Protein
ATP-dependent Clp protease proteolytic subunit, mitochondrial / Endopeptidase Clp


Mass: 24179.875 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLPP / Production host: Escherichia coli (E. coli) / References: UniProt: Q16740, endopeptidase Clp
#2: Chemical
ChemComp-OY9 / 3-({3-[(4-chlorophenyl)methyl]-4-oxo-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4H)-yl}methyl)benzonitrile


Mass: 390.865 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C22H19ClN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.96 Å3/Da / Density % sol: 58.49 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / Details: 0.1 M sodium acetate, 5% PEG 4000 / PH range: 4.6 - 5.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08B1-1 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 3.24→50 Å / Num. obs: 30288 / % possible obs: 98.7 % / Redundancy: 6.6 % / Biso Wilson estimate: 60.87 Å2 / Rmerge(I) obs: 0.286 / Rpim(I) all: 0.119 / Rrim(I) all: 0.31 / Χ2: 0.505 / Net I/σ(I): 1.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3.3-3.366.10.94314490.570.4051.0280.41996.6
3.36-3.426.10.84115040.6290.3660.9190.41397.1
3.42-3.485.90.81414820.6540.3610.8920.43497.7
3.48-3.556.50.68114910.8080.2850.740.41698.3
3.55-3.636.80.62115300.8620.2520.6710.43298.3
3.63-3.726.70.53314770.8990.2190.5770.46998.4
3.72-3.816.50.4615170.8880.1930.50.46998.7
3.81-3.916.30.45115180.8970.1950.4920.47598.5
3.91-4.0370.39414870.9530.1580.4250.49898.7
4.03-4.1670.35615360.9880.1440.3840.47598.8
4.16-4.3170.314870.9660.1210.3230.52699
4.31-4.486.90.25115320.9690.1020.2710.54199
4.48-4.686.70.23715110.9880.0980.2570.52499.1
4.68-4.936.30.215340.9740.0860.2180.56799.1
4.93-5.246.90.24215230.9750.0970.2610.50399.2
5.24-5.646.70.25615290.9670.1060.2780.49799.4
5.64-6.216.60.25215460.970.1050.2740.49399.4
6.21-7.170.20415320.9860.0820.220.50899.4
7.1-8.946.50.12915280.9910.0540.1410.59598.8
8.94-506.80.08215750.9960.0330.0880.899.8

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Processing

Software
NameVersionClassification
PHENIX1.19_4092refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BBA

6bba


Resolution: 3.24→48.47 Å / SU ML: 0.45 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2608 2000 6.61 %
Rwork0.1899 28263 -
obs0.1945 30263 96.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 123.02 Å2 / Biso mean: 49.0438 Å2 / Biso min: 12.61 Å2
Refinement stepCycle: final / Resolution: 3.24→48.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9732 0 196 125 10053
Biso mean--48.32 38.96 -
Num. residues----1249
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.24-3.320.3331030.25151455155870
3.32-3.410.34881420.24122010215297
3.41-3.510.29061440.2142042218698
3.51-3.620.27931450.20452034217998
3.62-3.750.28921460.20272068221499
3.75-3.90.26661450.19142058220399
3.9-4.080.2551440.18042034217899
4.08-4.290.23841460.16422071221799
4.29-4.560.23081460.16432066221299
4.56-4.920.23921470.15982072221999
4.92-5.410.26561460.19092064221099
5.41-6.190.27461480.19972100224899
6.19-7.790.21651470.18962072221999
7.8-48.470.25181510.19152117226899

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