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- PDB-3ovx: Cathepsin S in complex with a covalent inhibitor with an aldehyde... -

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Basic information

Entry
Database: PDB / ID: 3ovx
TitleCathepsin S in complex with a covalent inhibitor with an aldehyde warhead
ComponentsCathepsin S
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Cathepsin S / Hydrolase / Covalent inhibitor / aldehyde warhead / Ligand is covalently bound to Cys25 / Lysosomeal protein / 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 / positive regulation of apoptotic signaling pathway / collagen binding / MHC class II antigen presentation / Degradation of the extracellular matrix / proteolysis involved in protein catabolic process / lysosomal lumen / 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 / ficolin-1-rich granule lumen / adaptive immune response / 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-O64 / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.49 Å
AuthorsFradera, X. / van Zeeland, M. / Uitdehaag, J.C.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.
Authors: Cai, J. / Robinson, J. / Belshaw, S. / Everett, K. / Fradera, X. / van Zeeland, M. / van Berkom, L. / van Rijnsbergen, P. / Popplestone, L. / Baugh, M. / Dempster, M. / Bruin, J. / Hamilton, ...Authors: Cai, J. / Robinson, J. / Belshaw, S. / Everett, K. / Fradera, X. / van Zeeland, M. / van Berkom, L. / van Rijnsbergen, P. / Popplestone, L. / Baugh, M. / Dempster, M. / Bruin, J. / Hamilton, W. / Kinghorn, E. / Westwood, P. / Kerr, J. / Rankovic, Z. / Arbuckle, W. / Bennett, D.J. / Jones, P.S. / Long, C. / Martin, I. / Uitdehaag, J.C. / Meulemans, T.
History
DepositionSep 17, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 3, 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 / 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)48,9065
Polymers48,2402
Non-polymers6653
Water7,044391
1
A: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,4923
Polymers24,1201
Non-polymers3722
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,4142
Polymers24,1201
Non-polymers2941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.545, 85.545, 150.571
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-359-

HOH

21A-417-

HOH

31B-383-

HOH

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Components

#1: Protein Cathepsin S /


Mass: 24120.094 Da / Num. of mol.: 2 / Fragment: UNP residues 114-331
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSS / References: UniProt: P25774, cathepsin S
#2: Chemical ChemComp-O64 / 2-chloro-N-[(1S)-1-formylpropyl]-3-(trifluoromethyl)benzamide


Mass: 293.669 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H11ClF3NO2
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 391 / 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: 2.86 Å3/Da / Density % sol: 56.92 %
Crystal growTemperature: 298 K / Method: soaking cat s crystals / pH: 5
Details: Composition of crystallisation solution (including components from protein prep) 50 mM NaAcetate; 0.25 M NaCl; 4 mM MMTS: 26% PEG 4K; 0.1 M NaCitrate pH=5.0; 0,2 M (NH4)2SO4; 10 mM DMSO; 10 ...Details: Composition of crystallisation solution (including components from protein prep) 50 mM NaAcetate; 0.25 M NaCl; 4 mM MMTS: 26% PEG 4K; 0.1 M NaCitrate pH=5.0; 0,2 M (NH4)2SO4; 10 mM DMSO; 10 mM DTT Crystallisation method and temperature Hanging drop; RT Cryoprotectant composition 30% PEG 4K, 0.1 M NaCitrate pH=5.0; 0.2 M (NH4)2SO4; 15% PEG 400 (+ 10% compound) , soaking cat S crystals, temperature 298K

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Data collection

Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU
DetectorType: RAXIS-IV++ / Detector: CCD / Date: Mar 19, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.49→74.38 Å / Num. obs: 83072 / % possible obs: 89.8 % / Observed criterion σ(I): 1.1 / Rmerge(I) obs: 0.082

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.2.0019refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In-house cathepsin S structure

Resolution: 1.49→74.38 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.949 / SU B: 1.347 / SU ML: 0.051 / Cross valid method: THROUGHOUT / ESU R Free: 0.079 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22614 4178 5 %RANDOM
Rwork0.20037 ---
obs0.20168 78873 89.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 13.608 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.49→74.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3372 0 42 391 3805
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0223582
X-RAY DIFFRACTIONr_bond_other_d0.0010.022450
X-RAY DIFFRACTIONr_angle_refined_deg1.1951.9584860
X-RAY DIFFRACTIONr_angle_other_deg0.8333.0055941
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4235454
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.88124.251167
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.04415585
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.411517
X-RAY DIFFRACTIONr_chiral_restr0.0710.2492
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024072
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02755
X-RAY DIFFRACTIONr_nbd_refined0.2020.2721
X-RAY DIFFRACTIONr_nbd_other0.190.22611
X-RAY DIFFRACTIONr_nbtor_refined0.180.21791
X-RAY DIFFRACTIONr_nbtor_other0.0830.21681
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1030.2257
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2570.215
X-RAY DIFFRACTIONr_symmetry_vdw_other0.330.239
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1160.221
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9081.52807
X-RAY DIFFRACTIONr_mcbond_other0.1771.5909
X-RAY DIFFRACTIONr_mcangle_it1.05423478
X-RAY DIFFRACTIONr_scbond_it2.00331744
X-RAY DIFFRACTIONr_scangle_it2.7364.51371
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.49→1.525 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.471 100 -
Rwork0.384 1788 -
obs--28.02 %

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