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- PDB-7uvn: Crystal structure of human ClpP protease in complex with TR-57 -

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Basic information

Entry
Database: PDB / ID: 7uvn
TitleCrystal structure of human ClpP protease in complex with TR-57
ComponentsATP-dependent Clp protease proteolytic subunit, mitochondrial
KeywordsHYDROLASE/AGONIST / agonist / protease / degradation / apoptosis / 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-P3O / ATP-dependent Clp protease proteolytic subunit, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.11 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 2.0Feb 22, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / entity ...atom_site / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_contact_author / pdbx_distant_solvent_atoms / pdbx_initial_refinement_model / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly_prop / pdbx_struct_sheet_hbond / pdbx_struct_special_symmetry / pdbx_unobs_or_zero_occ_residues / refine / refine_hist / refine_ls_shell / struct_conf / struct_ref / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range
Item: _entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code ..._entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.pdbx_end_seq_num / _pdbx_distant_solvent_atoms.auth_asym_id / _pdbx_distant_solvent_atoms.auth_seq_id / _pdbx_distant_solvent_atoms.neighbor_macromolecule_distance / _pdbx_nonpoly_scheme.asym_id / _pdbx_nonpoly_scheme.auth_mon_id / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_nonpoly_scheme.ndb_seq_num / _pdbx_nonpoly_scheme.pdb_seq_num / _pdbx_nonpoly_scheme.pdb_strand_id / _pdbx_struct_assembly_prop.value / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_struct_special_symmetry.auth_seq_id / _refine.B_iso_max / _refine.B_iso_mean / _refine.B_iso_min / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.ls_number_reflns_R_work / _refine_hist.cycle_id / _refine_hist.number_atoms_total / _refine_hist.pdbx_B_iso_mean_ligand / _refine_hist.pdbx_B_iso_mean_solvent / _refine_hist.pdbx_number_atoms_protein / _refine_hist.pdbx_number_residues_total / _refine_ls_shell.R_factor_R_free_error / _refine_ls_shell.number_reflns_all / _refine_ls_shell.pdbx_total_number_of_bins_used / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.seq_align_end / _struct_ref_seq_dif.pdbx_auth_seq_num / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id
Description: Sequence discrepancy
Details: I removed Pro57 residues from previous model due to discrepancy with the real/cloning sequence (Ser57). However, the electron density for Ser57 is not very clear, so it was deleted in each ...Details: I removed Pro57 residues from previous model due to discrepancy with the real/cloning sequence (Ser57). However, the electron density for Ser57 is not very clear, so it was deleted in each chain. The model now agrees with the submitted sequence.
Provider: author / Type: Coordinate replacement
Revision 2.1Mar 1, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year
Revision 2.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)172,20514
Polymers169,2597
Non-polymers2,9467
Water4,288238
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)344,41128
Polymers338,51814
Non-polymers5,89214
Water25214
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,y,-z1
Buried area55390 Å2
ΔGint-290 kcal/mol
Surface area83780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.098, 153.040, 104.696
Angle α, β, γ (deg.)90.00, 117.92, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-431-

HOH

21C-434-

HOH

31G-425-

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-P3O / 3-({3-[(4-chlorophenyl)methyl]-1-methyl-2,4-dioxo-1,3,4,5,7,8-hexahydropyrido[4,3-d]pyrimidin-6(2H)-yl}methyl)benzonitrile


Mass: 420.891 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C23H21ClN4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 238 / 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: 2.99 Å3/Da / Density % sol: 58.89 %
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: 0.98 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: 0.98 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. obs: 35316 / % possible obs: 99.7 % / Redundancy: 7.2 % / Biso Wilson estimate: 63.45 Å2 / Rmerge(I) obs: 0.285 / Rpim(I) all: 0.113 / Rrim(I) all: 0.307 / Χ2: 0.857 / Net I/σ(I): 2.6 / Num. measured all: 253214
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3.1-3.157.31.06517620.7050.4191.1460.44399.4
3.15-3.2171.10217310.6340.441.1890.44499.5
3.21-3.276.71.00917820.660.4191.0940.46399.7
3.27-3.346.70.89917410.6950.3710.9740.46299.7
3.34-3.417.30.90517320.7590.3540.9730.599.7
3.41-3.497.40.72717620.9720.2850.7820.65999.6
3.49-3.587.50.61717920.8960.240.6630.5399.7
3.58-3.687.50.45717510.9130.1770.4910.7699.9
3.68-3.787.20.417630.9340.1580.4310.62199.8
3.78-3.9170.37517480.9360.1510.4050.82599.8
3.91-4.046.60.34317780.9490.1440.3720.72899.9
4.04-4.217.30.25617770.9910.10.2750.84799.9
4.21-4.47.50.20617310.980.0790.2210.95499.9
4.4-4.637.20.217730.9930.0790.2151.09499.9
4.63-4.926.80.17817850.9830.0730.1931.18299.7
4.92-5.37.40.21917690.9760.0850.2360.9199.9
5.3-5.837.50.21217720.980.0820.2280.91699.8
5.83-6.677.20.19117720.9860.0750.2050.95499.6
6.67-8.47.20.14117770.9880.0560.1521.42699.4
8.4-507.10.10318180.9960.0410.1112.34899.9

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Processing

Software
NameVersionClassification
PHENIX1.2refinement
PDB_EXTRACT3.27data extraction
MOSFLMdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BBA

6bba


Resolution: 3.11→49.25 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 28.57 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.283 1999 5.7 %
Rwork0.229 --
obs0.232 35043 98.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51.45 Å2
Refinement stepCycle: LAST / Resolution: 3.11→49.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9764 0 210 238 10212
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.11-3.180.34331240.26592053X-RAY DIFFRACTION86
3.18-3.270.30651450.25572401X-RAY DIFFRACTION98
3.27-3.370.34391430.25062349X-RAY DIFFRACTION99
3.37-3.470.32011420.25212353X-RAY DIFFRACTION98
3.47-3.60.30161430.2492374X-RAY DIFFRACTION99
3.6-3.740.3381430.25262377X-RAY DIFFRACTION99
3.74-3.910.2711440.22032368X-RAY DIFFRACTION99
3.91-4.120.27711430.21932376X-RAY DIFFRACTION99
4.12-4.380.2521460.20562416X-RAY DIFFRACTION100
4.38-4.710.24021440.19772380X-RAY DIFFRACTION99
4.71-5.190.26111450.21212381X-RAY DIFFRACTION99
5.19-5.940.30981450.25032394X-RAY DIFFRACTION99
5.94-7.480.30411440.24222394X-RAY DIFFRACTION99
7.48-49.250.24471480.22212428X-RAY DIFFRACTION99

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