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- PDB-7uvr: Crystal structure of human ClpP protease in complex with TR-65 -

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Basic information

Entry
Database: PDB / ID: 7uvr
TitleCrystal structure of human ClpP protease in complex with TR-65
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 / 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-PJF / ATP-dependent Clp protease proteolytic subunit, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.86 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)172,28314
Polymers169,2597
Non-polymers3,0237
Water1,982110
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)344,56528
Polymers338,51814
Non-polymers6,04714
Water25214
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area51290 Å2
ΔGint-228 kcal/mol
Surface area84430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.171, 152.515, 104.268
Angle α, β, γ (deg.)90.000, 118.100, 90.000
Int Tables number5
Space group name H-MC121

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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-PJF / 3-{[(10R)-4-[(4-chlorophenyl)methyl]-5-oxo-1,2,4,5,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-7(6H)-yl]methyl}benzonitrile


Mass: 431.917 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C24H22ClN5O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 110 / 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: 58.4 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / Details: 0.1 M 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: 0.9201 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.86→29.35 Å / Num. obs: 44929 / % possible obs: 99.2 % / Redundancy: 5.2 % / CC1/2: 0.987 / Rmerge(I) obs: 0.207 / Net I/σ(I): 6
Reflection shellResolution: 2.86→2.93 Å / Num. unique obs: 44929 / CC1/2: 0.628

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BBA

6bba


Resolution: 2.86→29.35 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 26.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2526 1997 4.45 %
Rwork0.2029 42895 -
obs0.2052 44892 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 101.1 Å2 / Biso mean: 46.9036 Å2 / Biso min: 21.92 Å2
Refinement stepCycle: final / Resolution: 2.86→29.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9536 0 217 110 9863
Biso mean--45.34 41.28 -
Num. residues----1222
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 (%)
2.86-2.930.3021370.26412931306895
2.93-3.010.28221420.250630393181100
3.01-3.10.29451430.237330873230100
3.1-3.20.27331430.22430593202100
3.2-3.320.33631420.21730643206100
3.32-3.450.23981440.214830763220100
3.45-3.60.25451430.214730763219100
3.61-3.790.28271430.189130563199100
3.79-4.030.23681430.190330933236100
4.03-4.340.23581440.174630863230100
4.34-4.780.2161410.16983027316899
4.78-5.460.26151440.191231043248100
5.47-6.870.25961440.224930793223100
6.87-29.350.2151440.20083118326299

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