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- PDB-3iej: Pyrazole-based Cathepsin S Inhibitors with Arylalkynes as P1 Bind... -

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Basic information

Entry
Database: PDB / ID: 3iej
TitlePyrazole-based Cathepsin S Inhibitors with Arylalkynes as P1 Binding Elements
ComponentsCathepsin S
KeywordsHYDROLASE / CATHEPSIN S / Disulfide bond / Glycoprotein / Lysosome / Polymorphism / Protease / Thiol protease / Zymogen
Function / homology
Function and homology information


cathepsin S / regulation of antigen processing and presentation / 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 ...cathepsin S / regulation of antigen processing and presentation / 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 / fibronectin binding / collagen catabolic process / extracellular matrix disassembly / laminin binding / phagocytic vesicle / collagen binding / Degradation of the extracellular matrix / MHC class II antigen presentation / cysteine-type peptidase activity / lysosomal lumen / proteolysis involved in protein catabolic process / Endosomal/Vacuolar pathway / protein processing / antigen processing and presentation of exogenous peptide antigen via MHC class II / tertiary granule lumen / late endosome / : / adaptive immune response / ficolin-1-rich granule lumen / lysosome / immune response / serine-type endopeptidase activity / cysteine-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-599 / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.18 Å
AuthorsBembenek, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements.
Authors: Ameriks, M.K. / Axe, F.U. / Bembenek, S.D. / Edwards, J.P. / Gu, Y. / Karlsson, L. / Randal, M. / Sun, S. / Thurmond, R.L. / Zhu, J.
History
DepositionJul 22, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 27, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)49,9704
Polymers48,8632
Non-polymers1,1072
Water3,459192
1
A: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9852
Polymers24,4311
Non-polymers5531
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9852
Polymers24,4311
Non-polymers5531
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)113.264, 37.192, 105.863
Angle α, β, γ (deg.)90.00, 108.59, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21A

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: GLN / End label comp-ID: GLN / Refine code: 6 / Auth seq-ID: 0 - 219 / Label seq-ID: 2 - 221

Dom-IDAuth asym-IDLabel asym-ID
1BB
2AA

NCS oper: (Code: given
Matrix: (-0.9924, 0.008117, 0.1225), (0.00812, 1, -0.000477), (-0.1225, 0.000521, -0.9925)
Vector: 33.49, -3.561, 54.61)

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Components

#1: Protein Cathepsin S


Mass: 24431.367 Da / Num. of mol.: 2 / Mutation: C25S
Source method: isolated from a genetically manipulated source
Details: JNJ27120509 / Source: (gene. exp.) Homo sapiens (human) / Gene: CTSS / Production host: Escherichia coli (E. coli) / References: UniProt: P25774, cathepsin S
#2: Chemical ChemComp-599 / 2-[3-{4-chloro-3-[(4-chlorophenyl)ethynyl]phenyl}-1-(3-morpholin-4-ylpropyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2-oxoethanol


Mass: 553.479 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H30Cl2N4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 192 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.16 Å3/Da / Density % sol: 43.12 %
Crystal growpH: 4.56 / Details: pH 4.56

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97949
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 8, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.15→100.5 Å / Num. obs: 20453 / % possible obs: 92.4 % / Observed criterion σ(I): 0 / Redundancy: 3 % / Rmerge(I) obs: 0.17 / Net I/σ(I): 5.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: OTHER / Resolution: 2.18→50 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.879 / SU B: 6.75 / SU ML: 0.174 / Cross valid method: THROUGHOUT / ESU R: 0.383 / ESU R Free: 0.262 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.26307 1052 5.2 %RANDOM
Rwork0.18736 ---
obs0.19129 19371 91.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 13.905 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å20 Å2-0.91 Å2
2---0.4 Å20 Å2
3---0.14 Å2
Refinement stepCycle: LAST / Resolution: 2.18→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3420 0 76 192 3688
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0223595
X-RAY DIFFRACTIONr_bond_other_d0.0010.022433
X-RAY DIFFRACTIONr_angle_refined_deg1.4211.9684870
X-RAY DIFFRACTIONr_angle_other_deg0.913.0045894
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2045440
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.37224.444162
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.52515562
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1891514
X-RAY DIFFRACTIONr_chiral_restr0.0790.2485
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024076
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02748
X-RAY DIFFRACTIONr_nbd_refined0.190.2723
X-RAY DIFFRACTIONr_nbd_other0.1920.22527
X-RAY DIFFRACTIONr_nbtor_refined0.1830.21744
X-RAY DIFFRACTIONr_nbtor_other0.0870.21777
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1670.2189
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1990.219
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2160.243
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0570.22
X-RAY DIFFRACTIONr_mcbond_it0.7721.52352
X-RAY DIFFRACTIONr_mcangle_it1.17423467
X-RAY DIFFRACTIONr_scbond_it1.75531645
X-RAY DIFFRACTIONr_scangle_it2.5434.51403
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: B / Ens-ID: 1 / Number: 2884 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
loose positional0.325
loose thermal1.1710
LS refinement shellResolution: 2.18→2.234 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.383 42
Rwork0.272 979

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