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- PDB-3n3g: 4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsi... -

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Basic information

Entry
Database: PDB / ID: 3n3g
Title4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important
ComponentsCathepsin S
KeywordsHYDROLASE / Cathepsin S / covalent inhibitor
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 / antigen processing and presentation / cysteine-type endopeptidase activator activity involved in apoptotic process / fibronectin binding / collagen catabolic process / extracellular matrix disassembly / laminin binding / collagen binding / MHC class II antigen presentation / phagocytic vesicle / Degradation of the extracellular matrix / lysosomal lumen / proteolysis involved in protein catabolic process / Endosomal/Vacuolar pathway / positive regulation of apoptotic signaling 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 / intracellular membrane-bounded organelle / serine-type endopeptidase activity / 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-935 / Chem-93N / DI(HYDROXYETHYL)ETHER / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsFradera, X. / Uitdehaag, J.C.M. / van Zeeland, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: 4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important.
Authors: Cai, J. / Fradera, X. / van Zeeland, M. / Dempster, M. / Cameron, K.S. / Bennett, D.J. / Robinson, J. / Popplestone, L. / Baugh, M. / Westwood, P. / Bruin, J. / Hamilton, W. / Kinghorn, E. / ...Authors: Cai, J. / Fradera, X. / van Zeeland, M. / Dempster, M. / Cameron, K.S. / Bennett, D.J. / Robinson, J. / Popplestone, L. / Baugh, M. / Westwood, P. / Bruin, J. / Hamilton, W. / Kinghorn, E. / Long, C. / Uitdehaag, J.C.
History
DepositionMay 20, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 14, 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
A: Cathepsin S
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,69610
Polymers48,0142
Non-polymers1,6828
Water9,224512
1
A: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0025
Polymers24,0071
Non-polymers9954
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,6945
Polymers24,0071
Non-polymers6874
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)85.757, 85.757, 150.902
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
11B-218-

SO4

21A-308-

HOH

31A-335-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Cathepsin S


Mass: 24006.936 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSS / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): BTI-Tn-5B1-4 (Hi-5) / References: UniProt: P25774, cathepsin S

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Non-polymers , 7 types, 520 molecules

#2: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-935 / (E)-1-(6-{4-[3-(4-methylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}pyridin-2-yl)methanimine


Mass: 406.445 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H25F3N4O
#5: Chemical ChemComp-93N / 6-{4-[3-(4-methylpiperazin-1-yl)propoxy]-3-(trifluoromethyl)phenyl}pyridine-2-carbonitrile


Mass: 404.429 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23F3N4O
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 512 / 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: 2.89 Å3/Da / Density % sol: 57.43 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5
Details: crystallisation solution: 50 mM NaAcetate, 0.25 M NaCl, 4 mM MMTS, 30% PEG 4K, 0.1 M NaCitrate, 0,2 M (NH4)2SO4, 10 mM DMSO, 10 mM DTT. Cryoprotectant composition: 30% PEG 4K, 0.1 M ...Details: crystallisation solution: 50 mM NaAcetate, 0.25 M NaCl, 4 mM MMTS, 30% PEG 4K, 0.1 M NaCitrate, 0,2 M (NH4)2SO4, 10 mM DMSO, 10 mM DTT. Cryoprotectant composition: 30% PEG 4K, 0.1 M NaCitrate, 0.2 M (NH4)2SO4, 15% PEG 400 (+ 10% compound). Ligand was introduced by soaking crystals prepared with another compound, pH 5.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jul 12, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.6→85.75 Å / Num. obs: 65361 / % possible obs: 87.7 % / Redundancy: 5.28 % / Rmerge(I) obs: 0.166 / Χ2: 1 / Net I/σ(I): 5.3 / Scaling rejects: 2609
Reflection shellResolution: 1.6→1.66 Å / Redundancy: 1.41 % / Rmerge(I) obs: 0.501 / Mean I/σ(I) obs: 1.1 / Num. measured all: 2568 / Num. unique all: 1825 / Χ2: 0.84 / % possible all: 24.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
d*TREK9.5Ldata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
d*TREKdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→74.56 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.93 / WRfactor Rfree: 0.265 / WRfactor Rwork: 0.223 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.778 / SU B: 3.206 / SU ML: 0.101 / SU R Cruickshank DPI: 0.112 / SU Rfree: 0.114 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.114 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.264 3289 5 %RANDOM
Rwork0.223 ---
obs0.225 65283 87.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 60.83 Å2 / Biso mean: 24.555 Å2 / Biso min: 11.76 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å20 Å2
2---0.03 Å20 Å2
3---0.05 Å2
Refinement stepCycle: LAST / Resolution: 1.6→74.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3372 0 100 512 3984
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0223598
X-RAY DIFFRACTIONr_bond_other_d0.0020.022442
X-RAY DIFFRACTIONr_angle_refined_deg1.1451.9714873
X-RAY DIFFRACTIONr_angle_other_deg0.8713.0055911
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5915442
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.38824.485165
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.87315566
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.1671514
X-RAY DIFFRACTIONr_chiral_restr0.0620.2487
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024050
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02757
X-RAY DIFFRACTIONr_nbd_refined0.190.2682
X-RAY DIFFRACTIONr_nbd_other0.1890.22630
X-RAY DIFFRACTIONr_nbtor_refined0.180.21747
X-RAY DIFFRACTIONr_nbtor_other0.0850.21701
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.2367
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2140.212
X-RAY DIFFRACTIONr_symmetry_vdw_other0.250.250
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1670.232
X-RAY DIFFRACTIONr_mcbond_it0.5531.52244
X-RAY DIFFRACTIONr_mcbond_other0.1041.5901
X-RAY DIFFRACTIONr_mcangle_it0.83923442
X-RAY DIFFRACTIONr_scbond_it1.34731642
X-RAY DIFFRACTIONr_scangle_it1.9714.51426
LS refinement shellResolution: 1.6→1.645 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.546 53 -
Rwork0.471 986 -
all-1039 -
obs--19.18 %

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