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- PDB-7qbl: Structure of cathepsin K in complex with the 3-cyano-3-aza-beta-a... -

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Basic information

Entry
Database: PDB / ID: 7qbl
TitleStructure of cathepsin K in complex with the 3-cyano-3-aza-beta-amino acid inhibitor Gu2602
ComponentsCathepsin K
KeywordsHYDROLASE / Cathepsin K / Protease inhibitor / Cyanohydrazide warhead / Azadipeptide nitrile
Function / homology
Function and homology information


cathepsin K / negative regulation of cartilage development / 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 / collagen catabolic process ...cathepsin K / negative regulation of cartilage development / 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 / collagen catabolic process / fibronectin binding / extracellular matrix disassembly / bone resorption / mitophagy / collagen binding / Degradation of the extracellular matrix / MHC class II antigen presentation / cysteine-type peptidase activity / lysosomal lumen / proteolysis involved in protein catabolic process / lysosome / apical plasma membrane / external side of plasma membrane / serine-type endopeptidase activity / cysteine-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 / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 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 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 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

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Assembly

Deposited unit
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,8442
Polymers23,5231
Non-polymers3201
Water84747
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area9770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.737, 78.753, 31.070
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 23523.480 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: 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
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / Source method: isolated from a natural source / Formula: H2O
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: 1.84 Å3/Da / Density % sol: 33.13 %
Crystal growTemperature: 289 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: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54187 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: May 5, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 2→28.9 Å / Num. obs: 11829 / % possible obs: 96.5 % / Redundancy: 4.117 % / Biso Wilson estimate: 35.064 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.078 / Rrim(I) all: 0.089 / Χ2: 0.824 / Net I/σ(I): 12.39 / Num. measured all: 48700
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
2-2.124.0360.5922.537588192318800.8890.67497.8
2.12-2.274.2690.3564.197603181617810.9630.40498.1
2.27-2.454.370.265.527421170816980.9520.29499.4
2.45-2.684.3050.1847.416647156215440.9770.20898.8
2.68-34.2440.11211.535992144014120.9920.12798.1
3-3.453.9920.06718.794870130012200.9960.07793.8
3.45-4.222.8580.04126.78279810869790.9970.0590.1
4.22-5.914.3390.03834.8635758828240.9970.04393.4
5.91-28.94.4930.02939.622065454910.9990.03290.1

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7NXM

7nxm


Resolution: 2→28.9 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.9 / SU B: 8.156 / SU ML: 0.209 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.279 / ESU R Free: 0.229 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2858 598 5 %RANDOM
Rwork0.2173 ---
obs0.2207 11344 96.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 80.79 Å2 / Biso mean: 34.95 Å2 / Biso min: 19.14 Å2
Baniso -1Baniso -2Baniso -3
1--2.69 Å2-0 Å20 Å2
2--2.04 Å2-0 Å2
3---0.66 Å2
Refinement stepCycle: final / Resolution: 2→28.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1649 0 23 47 1719
Biso mean--43.28 32.98 -
Num. residues----215
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0131720
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171537
X-RAY DIFFRACTIONr_angle_refined_deg1.5941.6452322
X-RAY DIFFRACTIONr_angle_other_deg1.3111.5853582
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1945216
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.89522.96791
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.29915286
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.623158
X-RAY DIFFRACTIONr_chiral_restr0.070.2206
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021974
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02358
LS refinement shellResolution: 2→2.052 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.345 44 -
Rwork0.355 836 -
all-880 -
obs--99.66 %

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