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Basic information

Entry
Database: PDB / ID: 6iw7
Titlestructural insights into Mycobacterium tuberculosis ClpP1P2 inhibition by Cediranib: implications for developing antimicrobial agents targeting Clp protease
Components(ATP-dependent Clp protease proteolytic subunit ...) x 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Mycobacterium tuberculosis / antimicrobial agents / ClpP1P2 / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


endopeptidase Clp / endopeptidase Clp complex / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / ATPase binding / serine-type endopeptidase activity / cytoplasm
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-AV3 / LEUCINE / (2S)-2-benzamido-4-methyl-pentanoic acid / ATP-dependent Clp protease proteolytic subunit 2 / ATP-dependent Clp protease proteolytic subunit 1
Similarity search - Component
Biological speciesMycobacterium tuberculosis CDC1551 (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69212103413 Å
AuthorsBao, R. / Luo, Y.F. / Zhu, Y.B. / Yang, Y. / Zhou, Y.Z.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81473253 China
CitationJournal: To Be Published
Title: structural insights into Mycobacterium tuberculosis ClpP1P2 inhibition by Cediranib: implications for developing antimicrobial agents targeting Clp protease
Authors: Bao, R. / Luo, Y.F. / Zhu, Y.B. / Yang, Y. / Yang, T.
History
DepositionDec 4, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 2.0Apr 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Author supporting evidence / Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / audit_author ...atom_site / audit_author / cell / citation_author / computing / entity / entity_src_gen / pdbx_audit_support / pdbx_distant_solvent_atoms / pdbx_entity_instance_feature / pdbx_entry_details / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_sheet_hbond / pdbx_validate_close_contact / pdbx_validate_peptide_omega / pdbx_validate_rmsd_angle / pdbx_validate_torsion / refine / refine_hist / refine_ls_restr / refine_ls_shell / reflns / software / struct_conf / struct_conn / struct_sheet_range / struct_site / struct_site_gen / symmetry
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _audit_author.name / _cell.angle_beta / _cell.volume / _citation_author.name / _entity.src_method / _entity_src_gen.gene_src_strain / _entity_src_gen.pdbx_gene_src_scientific_name / _pdbx_audit_support.funding_organization / _pdbx_audit_support.grant_number / _pdbx_nonpoly_scheme.asym_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_gen.asym_id_list / _pdbx_struct_assembly_prop.value / _pdbx_struct_sheet_hbond.range_1_auth_atom_id / _pdbx_struct_sheet_hbond.range_1_auth_comp_id / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_atom_id / _pdbx_struct_sheet_hbond.range_1_label_comp_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_atom_id / _pdbx_struct_sheet_hbond.range_2_auth_comp_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_atom_id / _pdbx_struct_sheet_hbond.range_2_label_comp_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _refine.B_iso_mean / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.ls_d_res_high / _refine.ls_d_res_low / _refine.ls_number_reflns_R_work / _refine.ls_percent_reflns_R_free / _refine.ls_percent_reflns_obs / _refine.overall_SU_ML / _refine.pdbx_ls_sigma_F / _refine.pdbx_overall_phase_error / _refine.pdbx_stereochemistry_target_values / _refine_hist.d_res_high / _refine_hist.d_res_low / _refine_ls_restr.dev_ideal / _refine_ls_restr.number / _refine_ls_restr.type / _refine_ls_shell.R_factor_R_free / _refine_ls_shell.R_factor_R_work / _refine_ls_shell.d_res_high / _refine_ls_shell.d_res_low / _refine_ls_shell.percent_reflns_obs / _reflns.B_iso_Wilson_estimate / _software.version / _struct_conf.beg_auth_comp_id / _struct_conf.beg_auth_seq_id / _struct_conf.beg_label_comp_id / _struct_conf.beg_label_seq_id / _struct_conf.end_auth_comp_id / _struct_conf.end_auth_seq_id / _struct_conf.end_label_comp_id / _struct_conf.end_label_seq_id / _struct_conf.pdbx_PDB_helix_length / _struct_conn.pdbx_dist_value / _struct_sheet_range.beg_auth_comp_id / _struct_sheet_range.beg_auth_seq_id / _struct_sheet_range.beg_label_comp_id / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_auth_comp_id / _struct_sheet_range.end_auth_seq_id / _struct_sheet_range.end_label_comp_id / _struct_sheet_range.end_label_seq_id / _struct_site.details / _struct_site.id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id / _struct_site.pdbx_num_residues / _symmetry.space_group_name_Hall
Description: Ligand geometry / Provider: author / Type: Coordinate replacement
Revision 3.0Apr 19, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Other / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / cell ...atom_site / cell / chem_comp / database_2 / entity / entity_poly / entity_poly_seq / pdbx_entity_nonpoly / pdbx_entity_src_syn / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly_gen / pdbx_validate_close_contact / pdbx_validate_peptide_omega / struct_asym / struct_conn / struct_ref / struct_ref_seq / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.group_PDB / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.label_seq_id / _atom_site.type_symbol / _cell.Z_PDB / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_atom_id_1 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_seq_id / _struct_site_gen.label_asym_id
Revision 3.1Nov 29, 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 2
B: ATP-dependent Clp protease proteolytic subunit 1
C: ATP-dependent Clp protease proteolytic subunit 2
D: ATP-dependent Clp protease proteolytic subunit 1
F: ATP-dependent Clp protease proteolytic subunit 2
H: ATP-dependent Clp protease proteolytic subunit 2
I: ATP-dependent Clp protease proteolytic subunit 1
J: ATP-dependent Clp protease proteolytic subunit 2
K: ATP-dependent Clp protease proteolytic subunit 1
L: ATP-dependent Clp protease proteolytic subunit 2
M: ATP-dependent Clp protease proteolytic subunit 1
N: ATP-dependent Clp protease proteolytic subunit 1
E: ATP-dependent Clp protease proteolytic subunit 2
G: ATP-dependent Clp protease proteolytic subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)311,39349
Polymers303,10914
Non-polymers8,28435
Water3,369187
1
A: ATP-dependent Clp protease proteolytic subunit 2
B: ATP-dependent Clp protease proteolytic subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,9358
Polymers43,3012
Non-polymers1,6346
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3550 Å2
ΔGint-9 kcal/mol
Surface area19210 Å2
MethodPISA
2
C: ATP-dependent Clp protease proteolytic subunit 2
D: ATP-dependent Clp protease proteolytic subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4857
Polymers43,3012
Non-polymers1,1835
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3410 Å2
ΔGint-9 kcal/mol
Surface area18980 Å2
MethodPISA
3
F: ATP-dependent Clp protease proteolytic subunit 2
M: ATP-dependent Clp protease proteolytic subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0346
Polymers43,3012
Non-polymers7334
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3410 Å2
ΔGint-10 kcal/mol
Surface area18500 Å2
MethodPISA
4
H: ATP-dependent Clp protease proteolytic subunit 2
I: ATP-dependent Clp protease proteolytic subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4857
Polymers43,3012
Non-polymers1,1835
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3440 Å2
ΔGint-9 kcal/mol
Surface area18850 Å2
MethodPISA
5
J: ATP-dependent Clp protease proteolytic subunit 2
K: ATP-dependent Clp protease proteolytic subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4857
Polymers43,3012
Non-polymers1,1835
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-12 kcal/mol
Surface area18940 Å2
MethodPISA
6
L: ATP-dependent Clp protease proteolytic subunit 2
N: ATP-dependent Clp protease proteolytic subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4857
Polymers43,3012
Non-polymers1,1835
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3460 Å2
ΔGint-9 kcal/mol
Surface area18500 Å2
MethodPISA
7
E: ATP-dependent Clp protease proteolytic subunit 2
G: ATP-dependent Clp protease proteolytic subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4857
Polymers43,3012
Non-polymers1,1835
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3400 Å2
ΔGint-11 kcal/mol
Surface area18460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)210.634, 180.78, 95.926
Angle α, β, γ (deg.)90.0, 95.716, 90.0
Int Tables number5
Space group name H-MC121
Space group name HallC2y

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Components

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ATP-dependent Clp protease proteolytic subunit ... , 2 types, 14 molecules ACFHJLEBDIKMNG

#1: Protein
ATP-dependent Clp protease proteolytic subunit 2 / Endopeptidase Clp 2


Mass: 22235.328 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis CDC1551 (bacteria)
Strain: CDC 1551 / Gene: clpP2, MT2535 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P9WPC2, endopeptidase Clp
#2: Protein
ATP-dependent Clp protease proteolytic subunit 1 / Endopeptidase Clp 1


Mass: 21065.934 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis CDC1551 (bacteria)
Strain: CDC 1551 / Gene: clpP1, clpP, MT2536 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P9WPC4, endopeptidase Clp

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Non-polymers , 4 types, 222 molecules

#3: Chemical
ChemComp-S0R / (2S)-2-benzamido-4-methyl-pentanoic acid


Type: L-peptide linking / Mass: 235.279 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C13H17NO3
#4: Chemical
ChemComp-LEU / LEUCINE


Type: L-peptide linking / Mass: 131.173 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C6H13NO2
#5: Chemical
ChemComp-AV3 / 4-[(4-fluoro-2-methyl-3H-indol-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]quinazoline / Cediranib


Mass: 450.505 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: C25H27FN4O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: anticancer, inhibitor*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 187 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.88 Å3/Da / Density % sol: 57.33 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 1.5 M Ammonium sulphate and 0.1 M MES pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.692→30 Å / Num. obs: 96900 / % possible obs: 98.6 % / Redundancy: 4.9 % / Biso Wilson estimate: 51.2743040041 Å2 / CC1/2: 0.376 / Net I/σ(I): 8.04
Reflection shellResolution: 2.692→3.025 Å / Num. unique obs: 9595 / CC1/2: 0.986

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5DZK

5dzk


Resolution: 2.69212103413→29.6991144947 Å / SU ML: 0.341053734419 / Cross valid method: NONE / σ(F): 1.33652883212 / Phase error: 25.9770708982
RfactorNum. reflection% reflection
Rfree0.248702480182 1997 2.06514994829 %
Rwork0.191866282274 94703 -
obs0.193049314558 96700 98.1028710561 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.4690821112 Å2
Refinement stepCycle: LAST / Resolution: 2.69212103413→29.6991144947 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms19747 0 581 187 20515
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011549785437820658
X-RAY DIFFRACTIONf_angle_d1.0786653543927960
X-RAY DIFFRACTIONf_chiral_restr0.05021609813693217
X-RAY DIFFRACTIONf_plane_restr0.004469501232933600
X-RAY DIFFRACTIONf_dihedral_angle_d15.10054519537608
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.693-2.75940.3285845181391350.2474246822416363X-RAY DIFFRACTION92.6564950806
2.7594-2.83390.3370020047261440.2605003895216792X-RAY DIFFRACTION98.3969357356
2.8339-2.91730.3208550782761420.2620360469196756X-RAY DIFFRACTION98.7827581269
2.9173-3.01130.3296438294581450.2649602445486866X-RAY DIFFRACTION99.0954063604
3.0113-3.11890.3224393744351430.2653952042866794X-RAY DIFFRACTION99.227578315
3.1189-3.24360.303849949711430.2330584217656810X-RAY DIFFRACTION99.3001999429
3.2436-3.3910.2823632692851440.2130090756146830X-RAY DIFFRACTION99.1893045086
3.391-3.56950.2563854438461440.1995990130596830X-RAY DIFFRACTION99.0484306207
3.5695-3.79270.2466559860541430.1688124772586775X-RAY DIFFRACTION98.729841587
3.7927-4.08490.19569697221440.1537353982186812X-RAY DIFFRACTION98.554831397
4.0849-4.49470.1818831025431430.1369948478186803X-RAY DIFFRACTION98.6227459889
4.4947-5.14220.2036348333641430.1505718146486799X-RAY DIFFRACTION98.2729331823
5.1422-6.46760.2765067089121430.2097930704326764X-RAY DIFFRACTION97.7636234961
6.4676-29.690.21850258911410.18260045386709X-RAY DIFFRACTION95.8444102421

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