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- PDB-3kw9: X-ray structure of Cathepsin K covalently bound to a triazine ligand -

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Basic information

Entry
Database: PDB / ID: 3kw9
TitleX-ray structure of Cathepsin K covalently bound to a triazine ligand
ComponentsCathepsin K
KeywordsHYDROLASE / cysteine / thioimidate / Disulfide bond / cys protease / inhibitor / non-peptide / Protease / Thiol protease / Zymogen
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 / Collagen degradation / fibronectin binding / collagen catabolic process / extracellular matrix disassembly / cysteine-type peptidase activity / positive regulation of apoptotic signaling pathway / bone resorption / cellular response to transforming growth factor beta stimulus / collagen binding / MHC class II antigen presentation / Degradation of the extracellular matrix / proteolysis involved in protein catabolic process / lysosomal lumen / 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-ORG / trifluoroacetic acid / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsUitdehaag, J.C.M. / van Zeeland, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors.
Authors: Rankovic, Z. / Cai, J. / Kerr, J. / Fradera, X. / Robinson, J. / Mistry, A. / Hamilton, E. / McGarry, G. / Andrews, F. / Caulfield, W. / Cumming, I. / Dempster, M. / Waller, J. / Scullion, P. ...Authors: Rankovic, Z. / Cai, J. / Kerr, J. / Fradera, X. / Robinson, J. / Mistry, A. / Hamilton, E. / McGarry, G. / Andrews, F. / Caulfield, W. / Cumming, I. / Dempster, M. / Waller, J. / Scullion, P. / Martin, I. / Mitchell, A. / Long, C. / Baugh, M. / Westwood, P. / Kinghorn, E. / Bruin, J. / Hamilton, W. / Uitdehaag, J. / van Zeeland, M. / Potin, D. / Saniere, L. / Fouquet, A. / Chevallier, F. / Deronzier, H. / Dorleans, C. / Nicolai, E.
History
DepositionDec 1, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jun 19, 2013Group: Database references
Revision 1.3Nov 1, 2017Group: Refinement description / Category: software

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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)23,9253
Polymers23,5231
Non-polymers4012
Water1,69394
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.391, 55.391, 128.719
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 23523.480 Da / Num. of mol.: 1 / Fragment: UNP residues 115 to 329
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Organ (production host): ovary / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P43235, cathepsin K
#2: Chemical ChemComp-ORG / 4-(cyclohexylamino)-6-piperazin-1-yl-1,3,5-triazine-2-carbonitrile


Mass: 287.363 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H21N7
#3: Chemical ChemComp-TFA / trifluoroacetic acid / Trifluoroacetic acid


Mass: 114.023 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2HF3O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.1 Å3/Da / Density % sol: 41.39 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 2.9
Details: 30% PEG4000, 0.2M Ammoniumsulphate pH2.9 cryoprotectant: crystallisation solution + 10% PEG4000 , VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.931 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jun 1, 2003 / Details: mirrors
RadiationMonochromator: unknown / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 1.8→100 Å / Num. all: 35807 / Num. obs: 35772 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.083 / Χ2: 1.123 / Net I/σ(I): 7.4
Reflection shellResolution: 1.8→1.86 Å / Rmerge(I) obs: 0.983 / Mean I/σ(I) obs: 2.6 / Num. unique all: 3566 / Χ2: 1.076 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.005data extraction
ADSCQuantumdata collection
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→50 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.816 / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.259 1958 -RANDOM
Rwork0.23 ---
all0.233 19366 --
obs0.233 19308 99.7 %-
Displacement parametersBiso max: 66.76 Å2 / Biso mean: 25.485 Å2 / Biso min: 14.29 Å2
Refinement stepCycle: LAST / Resolution: 1.8→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1649 0 28 94 1771
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_d1.237
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_dihedral_angle_d23.42
X-RAY DIFFRACTIONc_improper_angle_d0.7309

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