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- PDB-7qbm: Structure of the activation intermediate of cathepsin K in comple... -

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Basic information

Entry
Database: PDB / ID: 7qbm
TitleStructure of the activation intermediate of cathepsin K in complex with the 3-cyano-3-aza-beta-amino acid inhibitor Gu2602
Components(Cathepsin K) x 2
KeywordsHYDROLASE / Cathepsin K / Protease inhibitor / Cyanohydrazide warhead / Azadipeptide nitrile
Function / homology
Function and homology information


cathepsin K / mononuclear cell differentiation / intramembranous ossification / negative regulation of cartilage development / cellular response to zinc ion starvation / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / thyroid hormone generation / Trafficking and processing of endosomal TLR / proteoglycan binding ...cathepsin K / mononuclear cell differentiation / intramembranous ossification / negative regulation of cartilage development / cellular response to zinc ion starvation / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / thyroid hormone generation / Trafficking and processing of endosomal TLR / proteoglycan binding / Activation of Matrix Metalloproteinases / Collagen degradation / fibronectin binding / collagen catabolic process / extracellular matrix disassembly / bone resorption / mitophagy / cellular response to transforming growth factor beta stimulus / collagen binding / Degradation of the extracellular matrix / MHC class II antigen presentation / cysteine-type peptidase activity / lysosomal lumen / proteolysis involved in protein catabolic process / response to insulin / : / cellular response to tumor necrosis factor / response to ethanol / lysosome / apical plasma membrane / external side of plasma membrane / cysteine-type endopeptidase activity / serine-type endopeptidase activity / intracellular membrane-bounded organelle / proteolysis / extracellular space / extracellular region / nucleoplasm
Similarity search - Function
Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Papain-like cysteine endopeptidase / Cysteine peptidase, asparagine active site / Eukaryotic thiol (cysteine) proteases asparagine active site. / Cysteine peptidase, histidine active site / Eukaryotic thiol (cysteine) proteases histidine active site. / : / Peptidase C1A, papain C-terminal ...Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Papain-like cysteine endopeptidase / Cysteine peptidase, asparagine active site / Eukaryotic thiol (cysteine) proteases asparagine active site. / Cysteine peptidase, histidine active site / Eukaryotic thiol (cysteine) proteases histidine active site. / : / Peptidase C1A, papain C-terminal / Papain family cysteine protease / Papain family cysteine protease / Cysteine proteinases / Cysteine peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Cathepsin B; Chain A / Papain-like cysteine peptidase superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-A0U / ACETATE ION / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsBenysek, J. / Busa, M. / Mares, M.
Funding support Czech Republic, 2items
OrganizationGrant numberCountry
European Regional Development FundChemBioDrug CZ.02.1.01/0.0/0.0/16_019/0000729 Czech Republic
Czech Academy of SciencesRVO 61388963 Czech Republic
CitationJournal: J Enzyme Inhib Med Chem / Year: 2022
Title: Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes.
Authors: Benysek, J. / Busa, M. / Rubesova, P. / Fanfrlik, J. / Lepsik, M. / Brynda, J. / Matouskova, Z. / Bartz, U. / Horn, M. / Gutschow, M. / Mares, M.
History
DepositionNov 19, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 2.0Jan 18, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Experimental preparation / Other / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / cell ...atom_site / cell / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / exptl_crystal / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_conn_angle / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_asym / struct_conf / struct_conn / struct_ref / struct_ref_seq / struct_sheet_range
Item: _atom_site.label_entity_id / _atom_site.label_seq_id ..._atom_site.label_entity_id / _atom_site.label_seq_id / _cell.Z_PDB / _exptl_crystal.density_Matthews / _exptl_crystal.density_percent_sol / _pdbx_entity_nonpoly.entity_id / _pdbx_nonpoly_scheme.entity_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_unobs_or_zero_occ_atoms.label_seq_id / _struct_asym.entity_id / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.ref_id / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id
Revision 2.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin K
P: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0645
Polymers32,6602
Non-polymers4043
Water4,089227
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2050 Å2
ΔGint-20 kcal/mol
Surface area13390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.283, 103.283, 55.464
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11P-546-

HOH

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Components

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Protein , 2 types, 2 molecules AP

#1: Protein Cathepsin K / Cathepsin O / Cathepsin O2 / Cathepsin X


Mass: 23680.674 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Production host: Komagataella phaffii GS115 (fungus) / References: UniProt: P43235, cathepsin K
#2: Protein Cathepsin K / Cathepsin O / Cathepsin O2 / Cathepsin X


Mass: 8979.196 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Production host: Komagataella phaffii GS115 (fungus) / References: UniProt: P43235, cathepsin K

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Non-polymers , 4 types, 230 molecules

#3: Chemical ChemComp-A0U / ~{tert}-butyl ~{N}-[iminomethyl-[2-[methyl-(phenylmethyl)amino]-2-oxidanylidene-ethyl]amino]carbamate


Mass: 320.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H24N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.1 Å3/Da / Density % sol: 41.38 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 10% PEG 8000, 20% ethylene glycol, 0.02 M sodium formate, 0.02 M ammonium acetate, 0.02 M trisodium citrate, 0.02 M sodium potassium L-tartrate, 0.02 M sodium oxamate, 0.1 M MES/imidazole pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.79→48.91 Å / Num. obs: 27424 / % possible obs: 94.5 % / Redundancy: 9.501 % / Biso Wilson estimate: 38.136 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.128 / Rrim(I) all: 0.135 / Χ2: 0.873 / Net I/σ(I): 10.69 / Num. measured all: 260542
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.79-1.93.6961.651.0113153460535590.5171.91677.3
1.9-2.035.350.8782.3521607433540390.7390.97493.2
2.03-2.199.0110.4835.3435324402439200.9290.51297.4
2.19-2.411.640.3129.2542603375836600.9750.32797.4
2.4-2.6811.7640.18513.3739656339133710.9890.19399.4
2.68-3.0911.9510.1217.3536153304430250.9940.12699.4
3.09-3.7812.840.09521.3833037257825730.9960.09999.8
3.78-5.3312.3390.10622.6325246205120460.9950.1199.8
5.33-48.9111.180.11821.5113763123512310.9890.12499.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
BUCCANEERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7NXM

7nxm


Resolution: 1.88→48.91 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.943 / SU B: 4.514 / SU ML: 0.125 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.155 / ESU R Free: 0.145 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.234 1213 4.9 %RANDOM
Rwork0.1904 ---
obs0.1926 23673 99.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 99.75 Å2 / Biso mean: 34.616 Å2 / Biso min: 19.49 Å2
Baniso -1Baniso -2Baniso -3
1--0.95 Å20 Å20 Å2
2---0.95 Å20 Å2
3---1.91 Å2
Refinement stepCycle: final / Resolution: 1.88→48.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2196 0 28 233 2457
Biso mean--50.4 40.89 -
Num. residues----283
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0132315
X-RAY DIFFRACTIONr_bond_other_d0.0040.0162106
X-RAY DIFFRACTIONr_angle_refined_deg1.4261.6413140
X-RAY DIFFRACTIONr_angle_other_deg1.381.5884839
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4595293
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.6522.946129
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.16915381
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7271512
X-RAY DIFFRACTIONr_chiral_restr0.0650.2285
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022727
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02561
LS refinement shellResolution: 1.88→1.929 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.377 84 -
Rwork0.375 1662 -
all-1746 -
obs--96.3 %

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