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- PDB-2hh5: Crystal Structure of Cathepsin S in complex with a Zinc mediated ... -

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Basic information

Entry
Database: PDB / ID: 2hh5
TitleCrystal Structure of Cathepsin S in complex with a Zinc mediated non-covalent arylaminoethyl amide
ComponentsCathepsin S
KeywordsHYDROLASE / Cathepsin S / noncovalent / inhibition / zinc / arylaminoethyl-amides
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-GNQ / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsSpraggon, G. / Hornsby, M. / Lesley, S.A. / Tully, D.C. / Harris, J.L. / Karenewsky, D.S.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers.
Authors: Tully, D.C. / Liu, H. / Chatterjee, A.K. / Alper, P.B. / Epple, R. / Williams, J.A. / Roberts, M.J. / Woodmansee, D.H. / Masick, B.T. / Tumanut, C. / Li, J. / Spraggon, G. / Hornsby, M. / ...Authors: Tully, D.C. / Liu, H. / Chatterjee, A.K. / Alper, P.B. / Epple, R. / Williams, J.A. / Roberts, M.J. / Woodmansee, D.H. / Masick, B.T. / Tumanut, C. / Li, J. / Spraggon, G. / Hornsby, M. / Chang, J. / Tuntland, T. / Hollenbeck, T. / Gordon, P. / Harris, J.L. / Karanewsky, D.S.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: heterocyclic P3.
Authors: Tully, D.C. / Liu, H. / Alper, P.B. / Chatterjee, A.K. / Epple, R. / Roberts, M.J. / Williams, J.A. / Nguyen, K.T. / Woodmansee, D.H. / Tumanut, C. / Li, J. / Spraggon, G. / Chang, J. / ...Authors: Tully, D.C. / Liu, H. / Alper, P.B. / Chatterjee, A.K. / Epple, R. / Roberts, M.J. / Williams, J.A. / Nguyen, K.T. / Woodmansee, D.H. / Tumanut, C. / Li, J. / Spraggon, G. / Chang, J. / Tuntland, T. / Harris, J.L. / Karanewsky, D.S.
History
DepositionJun 27, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 15, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 30, 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 / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_conn_type.id / _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
B: Cathepsin S
A: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,39112
Polymers48,7832
Non-polymers1,60910
Water5,206289
1
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1966
Polymers24,3911
Non-polymers8045
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1966
Polymers24,3911
Non-polymers8045
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)109.542, 109.542, 98.529
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11B-934-

HOH

21A-941-

HOH

31A-942-

HOH

DetailsThe biological assembly is a monomer - there are two monomers in the asymmetric unit.

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Components

#1: Protein Cathepsin S /


Mass: 24391.393 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSS / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25774, cathepsin S
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-GNQ / N-[(1R)-1-[(BENZYLSULFONYL)METHYL]-2-{[(1S)-1-METHYL-2-{[4-(TRIFLUOROMETHOXY)PHENYL]AMINO}ETHYL]AMINO}-2-OXOETHYL]MORPHOLINE-4-CARBOXAMIDE


Mass: 572.597 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H31F3N4O6S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 289 / 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: 2.33 Å3/Da / Density % sol: 47.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.2M ZnAcetate, 20% PEG-3350, 150mM Sodium Chloride, pH 7.0, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Sep 28, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→34.2 Å / Num. all: 38549 / Num. obs: 38549 / % possible obs: 99.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.7 % / Rmerge(I) obs: 0.064 / Rsym value: 0.064 / Net I/σ(I): 17.7
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.763 / Mean I/σ(I) obs: 1.3 / Num. unique all: 4514 / Rsym value: 0.763 / % possible all: 98.2

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
PROCESSdata reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2F1G

2f1g


Resolution: 1.8→34.2 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.951 / SU B: 3.355 / SU ML: 0.101 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.127 / ESU R Free: 0.126 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22015 2048 5 %RANDOM
Rwork0.17328 ---
all0.1757 38549 --
obs0.17567 38549 99.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 27.905 Å2
Baniso -1Baniso -2Baniso -3
1--0.72 Å2-0.36 Å20 Å2
2---0.72 Å20 Å2
3---1.08 Å2
Refinement stepCycle: LAST / Resolution: 1.8→34.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3372 0 96 289 3757
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0223554
X-RAY DIFFRACTIONr_bond_other_d0.0010.022996
X-RAY DIFFRACTIONr_angle_refined_deg1.5111.9724818
X-RAY DIFFRACTIONr_angle_other_deg0.76537016
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0185432
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.74424.375160
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.19715558
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5841514
X-RAY DIFFRACTIONr_chiral_restr0.1340.2486
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024006
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02752
X-RAY DIFFRACTIONr_nbd_refined0.2010.2861
X-RAY DIFFRACTIONr_nbd_other0.180.23424
X-RAY DIFFRACTIONr_nbtor_refined0.1910.21820
X-RAY DIFFRACTIONr_nbtor_other0.0870.21967
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1490.2267
X-RAY DIFFRACTIONr_metal_ion_refined0.1140.29
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2830.216
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2340.239
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1660.215
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.1090.21
X-RAY DIFFRACTIONr_mcbond_it1.42522738
X-RAY DIFFRACTIONr_mcbond_other0.32904
X-RAY DIFFRACTIONr_mcangle_it1.71333432
X-RAY DIFFRACTIONr_scbond_it3.34951729
X-RAY DIFFRACTIONr_scangle_it4.30381386
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.336 156 -
Rwork0.287 2803 -
obs--98.24 %

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