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- PDB-3kwb: Structure of CatK covalently bound to a dioxo-triazine inhibitor -

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Basic information

Entry
Database: PDB / ID: 3kwb
TitleStructure of CatK covalently bound to a dioxo-triazine inhibitor
ComponentsCathepsin K
KeywordsHYDROLASE / covalent bond / Cys 25 / thioimidate / Disease mutation / Disulfide bond / Glycoprotein / Lysosome / 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-ORH / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.02 Å
AuthorsUitdehaag, J.C.M. / van Zeeland, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Dioxo-triazines as a novel series of cathepsin K inhibitors
Authors: Rankovic, Z. / Cai, J. / Fradera, X. / Dempster, M. / Mistry, A. / Mitchell, A. / Long, C. / Hamilton, E. / King, A. / Boucharens, S. / Jamieson, C. / Gillespie, J. / Cumming, I. / ...Authors: Rankovic, Z. / Cai, J. / Fradera, X. / Dempster, M. / Mistry, A. / Mitchell, A. / Long, C. / Hamilton, E. / King, A. / Boucharens, S. / Jamieson, C. / Gillespie, J. / Cumming, I. / Uitdehaag, J. / van Zeeland, M.
History
DepositionDec 1, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 7, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
X: Cathepsin K
Y: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,8624
Polymers47,0472
Non-polymers8152
Water11,097616
1
X: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,9312
Polymers23,5231
Non-polymers4071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
Y: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,9312
Polymers23,5231
Non-polymers4071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)31.452, 69.338, 90.850
Angle α, β, γ (deg.)90.00, 98.83, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 23523.480 Da / Num. of mol.: 2 / Fragment: full length / Mutation: wild type
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-ORH / 3,5-dioxo-4-(3-piperidin-1-ylpropyl)-2-[3-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile


Mass: 407.390 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20F3N5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 616 / 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: 2.08 Å3/Da / Density % sol: 40.88 %
Crystal growTemperature: 298 K / pH: 3.4
Details: 30%(W/V) PEG 4000 and 150 mM Ammonium Sulfate pH 3.4 3 microliter of protein at 10 mg/ml and 2 microliter of reservoir solution. , VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Feb 13, 2004 / Details: MIRRORS
RadiationMonochromator: UNKNOWN / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.017→27.461 Å / Num. obs: 23819 / % possible obs: 93.1 % / Observed criterion σ(I): 0 / Redundancy: 2.3 % / Rmerge(I) obs: 0.068 / Rsym value: 0.068 / Net I/σ(I): 13
Reflection shellResolution: 2.01→2.12 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.181 / Mean I/σ(I) obs: 4.1 / Rsym value: 0.181 / % possible all: 82.7

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Processing

Software
NameVersionClassificationNB
SCALA3.1.20data scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
DENZOdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.02→27.47 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.908 / Occupancy max: 1 / Occupancy min: 1 / SU B: 4.329 / SU ML: 0.122 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.296 / ESU R Free: 0.194 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE
RfactorNum. reflection% reflectionSelection details
Rfree0.263 1219 5.1 %RANDOM
Rwork0.194 ---
obs0.202 23818 100 %-
all-25584 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 18.42 Å2
Baniso -1Baniso -2Baniso -3
1--0.39 Å20 Å2-0.33 Å2
2--1.24 Å20 Å2
3----0.95 Å2
Refinement stepCycle: LAST / Resolution: 2.02→27.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3257 0 58 616 3931
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0223394
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.2021.9624588
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg1.1675423
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.42825.097155
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.88115555
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9141514
X-RAY DIFFRACTIONr_chiral_restr0.0980.2458
X-RAY DIFFRACTIONr_gen_planes_refined0.0550.0212622
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2311.52092
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.07123317
X-RAY DIFFRACTIONr_scbond_it2.131302
X-RAY DIFFRACTIONr_scangle_it3.1924.51271
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.02→2.07 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.349 73 -
Rwork0.211 1517 -
obs--100 %

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