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- PDB-4x6h: Development of N-(Functionalized benzoyl)-homocycloleucyl-glycino... -

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Basic information

Entry
Database: PDB / ID: 4x6h
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-3XT / Chem-I37 / Cathepsin K
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1 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 23, 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

Downloads & links

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Assembly

Deposited unit
A: Cathepsin K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7399
Polymers23,5231
Non-polymers1,2158
Water5,224290
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area780 Å2
ΔGint-47 kcal/mol
Surface area10220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.439, 54.551, 88.015
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-3XT / 4-amino-3-fluoro-N-(1-{[(2Z)-2-iminoethyl]carbamoyl}cyclohexyl)benzamide


Mass: 320.362 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H21FN4O2
#3: Chemical ChemComp-I37 / 4-amino-N-{1-[(cyanomethyl)carbamoyl]cyclohexyl}-3-fluorobenzamide


Mass: 318.346 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H19FN4O2
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 290 / 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: 1.86 Å3/Da / Density % sol: 33.85 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 0.1 M Tri-Sodium Citrate, 2.4 M Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 1.000008 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000008 Å / Relative weight: 1
ReflectionHighest resolution: 1 Å / Num. obs: 92375 / % possible obs: 96.8 % / Observed criterion σ(I): -3 / Redundancy: 5.9 % / Biso Wilson estimate: 8.75 Å2 / Rmerge F obs: 0.999 / Rmerge(I) obs: 0.052 / Rrim(I) all: 0.057 / Χ2: 1.025 / Net I/σ(I): 15.89 / Num. measured all: 540950
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1-1.060.7780.5222.225272615236122480.59380.4
1.06-1.130.9310.3324.368116514391143890.366100
1.13-1.220.9720.2037.298083213374133680.223100
1.22-1.340.9870.14210.077561912383123750.15599.9
1.34-1.50.9940.09615.37222611189111860.105100
1.5-1.730.9970.06523.1563932996199530.07199.9
1.73-2.120.9980.04633.7552387845684380.05199.8
2.12-2.990.9990.03743.3240706662566080.04199.7
2.990.9990.03147.9821357383638100.03499.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1 Å46.37 Å
Translation1 Å46.37 Å

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Processing

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

1atk


Resolution: 1→33.668 Å / FOM work R set: 0.9145 / SU ML: 0.08 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 15.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1655 4618 5 %RANDOM
Rwork0.1548 87755 --
obs0.1553 92373 96.78 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 81.59 Å2 / Biso mean: 13.26 Å2 / Biso min: 5.67 Å2
Refinement stepCycle: final / Resolution: 1→33.668 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1649 0 59 290 1998
Biso mean--18.14 28.05 -
Num. residues----215
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0221885
X-RAY DIFFRACTIONf_angle_d2.2992574
X-RAY DIFFRACTIONf_chiral_restr0.144258
X-RAY DIFFRACTIONf_plane_restr0.015335
X-RAY DIFFRACTIONf_dihedral_angle_d17.091726
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.0002-1.01150.29591000.26311910201063
1.0115-1.02340.24761120.26042113222572
1.0234-1.03590.22721260.23962405253180
1.0359-1.0490.23171410.22522673281490
1.049-1.06280.22411560.204329703126100
1.0628-1.07740.20511590.202330133172100
1.0774-1.09280.19781560.188929783134100
1.0928-1.10910.20281580.18329983156100
1.1091-1.12640.18421560.180129693125100
1.1264-1.14490.16711590.175330113170100
1.1449-1.16460.17611560.166729743130100
1.1646-1.18580.16511590.162530153174100
1.1858-1.20860.13511580.161430003158100
1.2086-1.23330.17281580.162829963154100
1.2333-1.26010.16921580.163630003158100
1.2601-1.28940.15381570.159929923149100
1.2894-1.32170.17861590.154830113170100
1.3217-1.35740.16091580.15630133171100
1.3574-1.39730.14661600.14930283188100
1.3973-1.44250.14521570.151530013158100
1.4425-1.4940.17871590.145630113170100
1.494-1.55380.13981580.148230073165100
1.5538-1.62450.14881600.141130333193100
1.6245-1.71020.14511610.138530523213100
1.7102-1.81730.15111600.141630533213100
1.8173-1.95760.15121600.139730363196100
1.9576-2.15460.15611610.13623058321999
2.1546-2.46630.14481620.14330843246100
2.4663-3.10690.16021630.15713098326199
3.1069-33.68680.1851710.15043253342499
Refinement TLS params.Method: refined / Origin x: 11.6481 Å / Origin y: -0.777 Å / Origin z: -12.016 Å
111213212223313233
T0.0528 Å20.0017 Å20.006 Å2-0.0573 Å20.0049 Å2--0.0571 Å2
L0.3523 °20.0988 °20.1219 °2-0.4862 °20.2097 °2--0.5231 °2
S0.0176 Å °-0.0104 Å °0.0099 Å °0.0252 Å °-0.015 Å °0.0123 Å °0.0198 Å °-0.0075 Å °-0.0019 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 301
2X-RAY DIFFRACTION1allB500 - 789
3X-RAY DIFFRACTION1allC790 - 795

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