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- PDB-3n4c: 6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S ... -

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Basic information

Entry
Database: PDB / ID: 3n4c
Title6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors
ComponentsCathepsin S
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Cathepsin S / covalent inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


cathepsin S / basement membrane disassembly / positive regulation of cation channel activity / antigen processing and presentation of peptide antigen / endolysosome lumen / response to acidic pH / cellular response to thyroid hormone stimulus / Trafficking and processing of endosomal TLR / proteoglycan binding / Assembly of collagen fibrils and other multimeric structures ...cathepsin S / basement membrane disassembly / positive regulation of cation channel activity / antigen processing and presentation of peptide antigen / endolysosome lumen / response to acidic pH / cellular response to thyroid hormone stimulus / Trafficking and processing of endosomal TLR / proteoglycan binding / Assembly of collagen fibrils and other multimeric structures / toll-like receptor signaling pathway / cysteine-type endopeptidase activator activity involved in apoptotic process / fibronectin binding / antigen processing and presentation / collagen catabolic process / extracellular matrix disassembly / laminin binding / phagocytic vesicle / 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 / Endosomal/Vacuolar pathway / protein processing / antigen processing and presentation of exogenous peptide antigen via MHC class II / late endosome / tertiary granule lumen / collagen-containing extracellular matrix / adaptive immune response / ficolin-1-rich granule lumen / lysosome / immune response / cysteine-type endopeptidase activity / serine-type endopeptidase activity / intracellular membrane-bounded organelle / Neutrophil degranulation / proteolysis / extracellular space / extracellular region
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-EF3 / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsFradera, X. / Uitdehaag, J.C.M. / van Zeeland, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: 6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors.
Authors: Cai, J. / Baugh, M. / Black, D. / Long, C. / Jonathan Bennett, D. / Dempster, M. / Fradera, X. / Gillespie, J. / Andrews, F. / Boucharens, S. / Bruin, J. / Cameron, K.S. / Cumming, I. / ...Authors: Cai, J. / Baugh, M. / Black, D. / Long, C. / Jonathan Bennett, D. / Dempster, M. / Fradera, X. / Gillespie, J. / Andrews, F. / Boucharens, S. / Bruin, J. / Cameron, K.S. / Cumming, I. / Hamilton, W. / Jones, P.S. / Kaptein, A. / Kinghorn, E. / Maidment, M. / Martin, I. / Mitchell, A. / Rankovic, Z. / Robinson, J. / Scullion, P. / Uitdehaag, J.C. / Vink, P. / Westwood, P. / van Zeeland, M. / van Berkom, L. / Bastiani, M. / Meulemans, T.
History
DepositionMay 21, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: 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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin S
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,1877
Polymers48,0142
Non-polymers1,1735
Water3,513195
1
A: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,5463
Polymers24,0071
Non-polymers5392
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,6424
Polymers24,0071
Non-polymers6353
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)85.629, 85.629, 150.573
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number91
Space group name H-MP4122
Components on special symmetry positions
IDModelComponents
11A-252-

HOH

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Components

#1: Protein Cathepsin S /


Mass: 24006.936 Da / Num. of mol.: 2 / Fragment: UNP residues 115 to 331
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: sapiens / Gene: CTSS, Homo sapiens / Plasmid: baculovirus / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): BTI-Tn-5B1-4 (Hi-5) / References: UniProt: P25774, cathepsin S
#2: Chemical ChemComp-EF3 / (E)-1-(1-methyl-6-{4-[3-(4-methylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}-1H-imidazo[4,5-c]pyridin-4-yl)methanimine


Mass: 460.495 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H27F3N6O
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 195 / 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: 2.87 Å3/Da / Density % sol: 57.21 %
Crystal growMethod: hanging drop / pH: 5
Details: Composition of crystallisation solution (including components from protein prep): 50 mM NaAcetate; 0.25 M NaCl; coconcentrated with inhibitor; 4% DMSO; 26% PEG 4K; 0.1 M NaCitrate pH=5.0; ...Details: Composition of crystallisation solution (including components from protein prep): 50 mM NaAcetate; 0.25 M NaCl; coconcentrated with inhibitor; 4% DMSO; 26% PEG 4K; 0.1 M NaCitrate pH=5.0; 0,2 M (NH4)2SO4. Cryoprotectant composition: 26% PEG 4K, 0.1 M NaCitrate pH=5.0; o0.2 M (NH4)2SO4; 15% PEG 400 (compound), Hanging drop, temperature room temperatureK

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Data collection

Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: R-Axis IV / Detector: CCD / Date: Dec 11, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→56.54 Å / Num. obs: 39256 / % possible obs: 87.4 % / Redundancy: 6.82 % / Rmerge(I) obs: 0.118 / Net I/σ(I): 8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obs% possible all
1.9-1.977.740.4823.390.9
1.97-2.057.680.423.790
2.05-2.147.550.3574.288.4
2.14-2.257.40.2994.886.7
2.25-2.397.130.2595.486.1
2.39-2.586.820.2056.383.6
2.58-2.846.440.1667.183.2
2.84-3.255.980.1179.482.4
3.25-4.095.070.07113.883.3
4.09-56.546.380.04523.599

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.14 Å56.54 Å
Translation2.14 Å56.54 Å

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Processing

Software
NameVersionClassificationNB
d*TREKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
d*TREKdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1MS6

1ms6


Resolution: 1.9→56.54 Å / Cor.coef. Fo:Fc: 0.916 / Cor.coef. Fo:Fc free: 0.883 / Occupancy max: 1 / Occupancy min: 0.2 / SU B: 3.519 / SU ML: 0.108 / SU R Cruickshank DPI: 0.158 / Cross valid method: THROUGHOUT / ESU R: 0.158 / ESU R Free: 0.181 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.28611 1968 5 %RANDOM
Rwork0.24907 ---
obs0.25091 37280 87.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.801 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å20 Å20 Å2
2---0.31 Å20 Å2
3---0.62 Å2
Refinement stepCycle: LAST / Resolution: 1.9→56.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3371 0 72 195 3638
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.369 156 -
Rwork0.363 2804 -
obs--90.63 %

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