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- PDB-4x6j: Development of N-(Functionalized benzoyl)-homocycloleucyl-glycino... -

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Basic information

Entry
Database: PDB / ID: 4x6j
TitleDevelopment of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors.
ComponentsCathepsin K
KeywordsHYDROLASE / cathepsin K / inhibitor
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 / cysteine-type peptidase activity / bone resorption / 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 / intracellular membrane-bounded organelle / serine-type endopeptidase activity / 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-3Y2 / : / S-1,2-PROPANEDIOL / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.59 Å
AuthorsBorisek, J. / Mohar, B. / Vizovisek, M. / Sosnowski, P. / Turk, D. / Turk, B. / Novic, M.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors.
Authors: Borisek, J. / Vizovisek, M. / Sosnowski, P. / Turk, B. / Turk, D. / Mohar, B. / Novic, M.
History
DepositionDec 8, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 9, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)24,2558
Polymers23,5231
Non-polymers7327
Water4,143230
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1070 Å2
ΔGint1 kcal/mol
Surface area10060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.219, 44.403, 51.354
Angle α, β, γ (deg.)90.000, 116.420, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 23523.480 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 115-329
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Production host: Komagataella pastoris GS115 (fungus) / References: UniProt: P43235, cathepsin K

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Non-polymers , 6 types, 237 molecules

#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#5: Chemical ChemComp-PGO / S-1,2-PROPANEDIOL


Mass: 76.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O2
#6: Chemical ChemComp-3Y2 / 2-amino-4-chloro-N-(1-{[(2E)-2-iminoethyl]carbamoyl}cyclohexyl)benzamide


Mass: 336.817 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H21ClN4O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 230 / 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: 2.05 Å3/Da / Density % sol: 39.99 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: Potassium chloride 0.2M, HEPES 0.05M, 5/4 PO/OH 35%

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5418 Å
DetectorType: Bruker Platinum 135 / Detector: CCD / Date: Jan 6, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.585→45.99 Å / Num. obs: 25360 / % possible obs: 97.53 % / Redundancy: 1.9 % / CC1/2: 0.991 / Rmerge(I) obs: 0.08534 / Net I/σ(I): 9.12
Reflection shellResolution: 1.585→1.642 Å / Redundancy: 1.8 % / Rmerge(I) obs: 1.124 / Mean I/σ(I) obs: 1.17 / CC1/2: 0.189 / % possible all: 90.01

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.59 Å16.86 Å
Translation1.59 Å16.86 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0069refinement
SCALEPACKdata scaling
PHASER2.5.6phasing
PDB_EXTRACT3.15data extraction
PROTEUM PLUSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ATK

1atk


Resolution: 1.59→45.99 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.927 / WRfactor Rfree: 0.2063 / WRfactor Rwork: 0.1554 / FOM work R set: 0.7596 / SU B: 2.833 / SU ML: 0.092 / SU R Cruickshank DPI: 0.1051 / SU Rfree: 0.1114 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.105 / ESU R Free: 0.111 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2376 1246 4.9 %RANDOM
Rwork0.1832 24114 --
obs0.1859 49603 97.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 55.04 Å2 / Biso mean: 18.432 Å2 / Biso min: 7.32 Å2
Baniso -1Baniso -2Baniso -3
1-0.41 Å2-0 Å20.51 Å2
2---0.6 Å2-0 Å2
3----0.22 Å2
Refinement stepCycle: final / Resolution: 1.59→45.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1649 0 46 230 1925
Biso mean--25.55 30.58 -
Num. residues----215
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.021824
X-RAY DIFFRACTIONr_bond_other_d0.0010.021723
X-RAY DIFFRACTIONr_angle_refined_deg1.9251.9712479
X-RAY DIFFRACTIONr_angle_other_deg1.4583.0013977
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4285244
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.79525.12282
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.6815310
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.253158
X-RAY DIFFRACTIONr_chiral_restr0.1120.2253
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212152
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02431
X-RAY DIFFRACTIONr_mcbond_it1.4931.55898
X-RAY DIFFRACTIONr_mcbond_other1.491.549897
X-RAY DIFFRACTIONr_mcangle_it2.1132.3221132
LS refinement shellResolution: 1.585→1.626 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.343 93 -
Rwork0.357 1593 -
all-1686 -
obs--87.95 %

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