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- PDB-7uw0: Crystal structure of human ClpP protease in complex with TR-133 -

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Basic information

Entry
Database: PDB / ID: 7uw0
TitleCrystal structure of human ClpP protease in complex with TR-133
ComponentsATP-dependent Clp protease proteolytic subunit, mitochondrial
KeywordsHYDROLASE/INHIBITOR / agonist / apoptosis / proteolysis / imipridone / cancer / HYDROLASE / HYDROLASE-INHIBITOR 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 / 2-enoyl-CoA Hydratase; Chain A, domain 1 / 2-enoyl-CoA Hydratase; Chain A, domain 1 / ClpP/crotonase-like domain superfamily ...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 / 2-enoyl-CoA Hydratase; Chain A, domain 1 / 2-enoyl-CoA Hydratase; Chain A, domain 1 / ClpP/crotonase-like domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-P4I / ATP-dependent Clp protease proteolytic subunit, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 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

Downloads & links

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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)172,30614
Polymers169,2597
Non-polymers3,0477
Water1,26170
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)344,61328
Polymers338,51814
Non-polymers6,09414
Water25214
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area54470 Å2
ΔGint-257 kcal/mol
Surface area83720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.660, 153.798, 133.208
Angle α, β, γ (deg.)90.000, 107.030, 90.000
Int Tables number5
Space group name H-MI121

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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-P4I / 3-({3-[(4-bromophenyl)methyl]-4-oxo-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4H)-yl}methyl)benzonitrile


Mass: 435.316 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C22H19BrN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 70 / 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: 3.07 Å3/Da / Density % sol: 59.91 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / Details: 0.1 sodium acetate, pH 4.6 to 5.2, 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: 2.8→93.62 Å / Num. obs: 47509 / % possible obs: 95.2 % / Redundancy: 4.9 % / CC1/2: 0.805 / Net I/σ(I): 4.2
Reflection shellResolution: 2.8→2.89 Å / Num. unique obs: 4706 / CC1/2: 0.42

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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: 2.8→51.69 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3088 1977 4.2 %
Rwork0.2603 45142 -
obs0.2623 47119 94.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 94.8 Å2 / Biso mean: 23.6987 Å2 / Biso min: 0.38 Å2
Refinement stepCycle: final / Resolution: 2.8→51.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9690 0 196 70 9956
Biso mean--24.08 13.09 -
Num. residues----1246
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 (%)
2.8-2.870.40261410.32233225336694
2.87-2.950.34711410.30993197333894
2.95-3.030.35561380.2623146328492
3.03-3.130.28651390.25643150328993
3.13-3.240.34041410.25353224336595
3.24-3.370.31311450.26183272341796
3.37-3.530.33421440.30263283342795
3.53-3.710.48611320.41143085321791
3.71-3.950.37661380.32013191332994
3.95-4.250.31991430.24223278342195
4.25-4.680.22211420.18243269341196
4.68-5.350.22061460.18713315346196
5.35-6.740.23321420.21643240338295
6.74-51.690.18831450.18353267341293

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