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- PDB-4x6i: Development of N-(Functionalized benzoyl)-homocycloleucyl-glycino... -

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Basic information

Entry
Database: PDB / ID: 4x6i
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 / 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-3Y1 / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.87 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 30, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 10, 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_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3837
Polymers23,5231
Non-polymers8606
Water3,621201
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area820 Å2
ΔGint-55 kcal/mol
Surface area9920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.459, 54.450, 87.870
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#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
#2: Chemical ChemComp-3Y1 / 2-amino-4-bromo-N-{1-[(cyanomethyl)carbamoyl]cyclohexyl}benzamide


Mass: 379.252 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H19BrN4O2
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 1.85 Å3/Da / Density % sol: 33.65 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: Lithium sulfate 0.2M, Sodium acetate 0.1M, Peg 8000 30%

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.54184 Å
DetectorType: Bruker Platinum 135 / Detector: CCD / Date: Jan 5, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54184 Å / Relative weight: 1
ReflectionResolution: 1.87→46.28 Å / Num. obs: 14804 / % possible obs: 98.31 % / Redundancy: 9.5 % / Rmerge(I) obs: 0.2593 / Net I/σ(I): 9.96
Reflection shellResolution: 1.87→1.937 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.9815 / % possible all: 98.16

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.67 Å54.45 Å
Translation1.67 Å54.45 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0069refinement
SCALEPACKdata scaling
PHASER2.5.6phasing
PDB_EXTRACT3.15data extraction
PROTEUM PLUS2011.4-1data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ATK

1atk


Resolution: 1.87→46.28 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.888 / WRfactor Rfree: 0.1988 / WRfactor Rwork: 0.1549 / FOM work R set: 0.8063 / SU B: 4.162 / SU ML: 0.12 / SU R Cruickshank DPI: 0.1887 / SU Rfree: 0.1671 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.189 / ESU R Free: 0.167 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.237 740 5 %RANDOM
Rwork0.181 ---
obs0.1838 14064 98.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 36.95 Å2 / Biso mean: 8.629 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.26 Å2-0 Å2-0 Å2
2---0.59 Å20 Å2
3---0.33 Å2
Refinement stepCycle: final / Resolution: 1.87→46.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3298 0 96 413 3807
Biso mean--17.03 16.32 -
Num. residues----430
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0191744
X-RAY DIFFRACTIONr_bond_other_d0.0010.021598
X-RAY DIFFRACTIONr_angle_refined_deg1.761.9742360
X-RAY DIFFRACTIONr_angle_other_deg0.90533686
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1155217
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.66925.12878
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.86615289
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.088157
X-RAY DIFFRACTIONr_chiral_restr0.1130.2239
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022017
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02408
X-RAY DIFFRACTIONr_mcbond_it0.6120.701863
X-RAY DIFFRACTIONr_mcbond_other0.6110.7862
X-RAY DIFFRACTIONr_mcangle_it1.0311.0471077
LS refinement shellResolution: 1.87→1.919 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 50 -
Rwork0.238 1026 -
all-1076 -
obs--98.35 %

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