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- PDB-3ovz: Cathepsin K in complex with a covalent inhibitor with a ketoamide... -

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Basic information

Entry
Database: PDB / ID: 3ovz
TitleCathepsin K in complex with a covalent inhibitor with a ketoamide warhead
ComponentsCathepsin K
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Cathepsin K / hydrolase / covalent inhibitor / ketoamide warhead / Ligand forms covalent bond to Cys25 / Lysosomes / HYDROLASE-HYDROLASE INHIBITOR complex
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 / thyroid hormone generation / endolysosome lumen / 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 / thyroid hormone generation / endolysosome lumen / Trafficking and processing of endosomal TLR / proteoglycan binding / Activation of Matrix Metalloproteinases / cysteine-type endopeptidase activator activity involved in apoptotic process / mitophagy / fibronectin binding / Collagen degradation / collagen catabolic process / extracellular matrix disassembly / bone resorption / cysteine-type peptidase activity / cellular response to transforming growth factor beta stimulus / collagen binding / MHC class II antigen presentation / Degradation of the extracellular matrix / lysosomal lumen / proteolysis involved in protein catabolic process / positive regulation of apoptotic signaling pathway / response to insulin / response to organic cyclic compound / cellular response to tumor necrosis factor / response to ethanol / lysosome / immune response / 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-O96 / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.02 Å
AuthorsFradera, X. / van Zeeland, M. / Uitdehaag, J.C.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.
Authors: Cai, J. / Robinson, J. / Belshaw, S. / Everett, K. / Fradera, X. / van Zeeland, M. / van Berkom, L. / van Rijnsbergen, P. / Popplestone, L. / Baugh, M. / Dempster, M. / Bruin, J. / Hamilton, ...Authors: Cai, J. / Robinson, J. / Belshaw, S. / Everett, K. / Fradera, X. / van Zeeland, M. / van Berkom, L. / van Rijnsbergen, P. / Popplestone, L. / Baugh, M. / Dempster, M. / Bruin, J. / Hamilton, W. / Kinghorn, E. / Westwood, P. / Kerr, J. / Rankovic, Z. / Arbuckle, W. / Bennett, D.J. / Jones, P.S. / Long, C. / Martin, I. / Uitdehaag, J.C. / Meulemans, T.
History
DepositionSep 17, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 12, 2011Group: Derived calculations
Revision 1.3May 9, 2012Group: Data collection
Revision 1.4Jan 31, 2018Group: Experimental preparation / Category: exptl_crystal_grow
Item: _exptl_crystal_grow.pdbx_details / _exptl_crystal_grow.temp
Revision 1.5Apr 3, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)23,9914
Polymers23,3551
Non-polymers6363
Water1,42379
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.741, 55.741, 128.916
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 23355.287 Da / Num. of mol.: 1 / Fragment: UNP residues 121-329
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / References: UniProt: P43235, cathepsin K
#2: Chemical ChemComp-O96 / N-[(1S)-3-amino-1-ethyl-2,3-dioxopropyl]-2-chloro-4-(pyridin-2-ylmethoxy)-3-(trifluoromethyl)benzamide


Mass: 443.804 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17ClF3N3O4
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 79 / Source method: isolated from a natural source / Formula: H2O

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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: 2.02 Å3/Da / Density % sol: 38.61 %
Crystal growTemperature: 298 K
Details: 0 mM NaAcetate pH=4.0, 0.3 M NaCl, 20% PEG4000, 0.2 M (NH4)2SO4, pH=2.9, 4% Methanol, Cryoprotectant composition:20% PEG4000, 0.1M (NH4)2SO4 pH=2.9, 4% Methanol, 20% PEG 400, pH 5, ...Details: 0 mM NaAcetate pH=4.0, 0.3 M NaCl, 20% PEG4000, 0.2 M (NH4)2SO4, pH=2.9, 4% Methanol, Cryoprotectant composition:20% PEG4000, 0.1M (NH4)2SO4 pH=2.9, 4% Methanol, 20% PEG 400, pH 5, cocrystallization, hanging drop, temperature 398K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 12, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.02→55.74 Å / Num. obs: 14051 / % possible obs: 100 %
Reflection shellResolution: 2.02→2.09 Å / Rmerge(I) obs: 0.7 / Mean I/σ(I) obs: 2 / % possible all: 100

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.2.0019refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In-house cathepsin K structure

Resolution: 2.02→51.16 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.902 / SU B: 7.597 / SU ML: 0.204 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rfree0.308 698 5 %
Rwork0.244 --
obs0.247 13991 99.7 %
Solvent computationSolvent model: MASK
Displacement parametersBiso mean: 35.26 Å2
Baniso -1Baniso -2Baniso -3
1-0.99 Å20 Å20 Å2
2--0.99 Å20 Å2
3----1.98 Å2
Refinement stepCycle: LAST / Resolution: 2.02→51.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1637 0 40 79 1756
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0221738
X-RAY DIFFRACTIONr_bond_other_d0.0020.021176
X-RAY DIFFRACTIONr_angle_refined_deg1.7851.9662355
X-RAY DIFFRACTIONr_angle_other_deg1.0523.0052859
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1985219
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.59225.36682
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.13815288
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.198157
X-RAY DIFFRACTIONr_chiral_restr0.1040.2236
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021976
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02344
X-RAY DIFFRACTIONr_nbd_refined0.2150.2355
X-RAY DIFFRACTIONr_nbd_other0.2110.21190
X-RAY DIFFRACTIONr_nbtor_refined0.1870.2824
X-RAY DIFFRACTIONr_nbtor_other0.0920.2878
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.160.284
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2760.221
X-RAY DIFFRACTIONr_symmetry_vdw_other0.30.248
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2570.27
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9171.51366
X-RAY DIFFRACTIONr_mcbond_other0.1711.5449
X-RAY DIFFRACTIONr_mcangle_it1.10621686
X-RAY DIFFRACTIONr_scbond_it1.8913831
X-RAY DIFFRACTIONr_scangle_it2.5024.5665
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.02→2.07 Å
RfactorNum. reflection% reflection
Rfree0.429 55 -
Rwork0.307 975 -
obs--100 %

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