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- PDB-2hhn: Cathepsin S in complex with non covalent arylaminoethyl amide. -

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Basic information

Entry
Database: PDB / ID: 2hhn
TitleCathepsin S in complex with non covalent arylaminoethyl amide.
ComponentsCathepsin S
KeywordsHYDROLASE / cathepsin S / noncovalent / inhibition / arylaminoethyl amide / protease
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-GNQ / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / RIGID BODY REFINEMENT / Resolution: 1.55 Å
AuthorsSpraggon, G. / Hornsby, M. / Lesley, S.A. / Tully, D.C. / Harris, J.L. / Karenewsky, D.S. / Kulathila, R. / Clark, K.
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: Nat.Struct.Mol.Biol. / Year: 1999
Title: Structural and mechanistic basis of immunity towards endonuclease colicins
Authors: Kleanthous, C. / Kuhlmann, U.C. / Pommer, A.J. / Ferguson, N. / Radford, S.E. / Moore, G.R. / James, R. / Hemmings, A.M.
History
DepositionJun 28, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software
Revision 1.4Aug 30, 2023Group: Advisory / Data collection ...Advisory / 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_unobs_or_zero_occ_atoms / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)49,7407
Polymers48,7832
Non-polymers9575
Water10,647591
1
A: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7765
Polymers24,3911
Non-polymers3844
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9642
Polymers24,3911
Non-polymers5731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
A: Cathepsin S
B: Cathepsin S
hetero molecules

A: Cathepsin S
B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,47914
Polymers97,5664
Non-polymers1,91410
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_565x,-y+1,-z+1/21
Buried area6650 Å2
ΔGint-120 kcal/mol
Surface area35440 Å2
MethodPISA
4
A: Cathepsin S
hetero molecules

A: Cathepsin S
hetero molecules

B: Cathepsin S
hetero molecules

B: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,47914
Polymers97,5664
Non-polymers1,91410
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_565x,-y+1,-z+1/21
crystal symmetry operation3_555-y,x,z+1/41
crystal symmetry operation8_565-y,-x+1,-z+1/41
Buried area5520 Å2
ΔGint-118 kcal/mol
Surface area36560 Å2
MethodPISA
5
A: Cathepsin S
hetero molecules

A: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,55110
Polymers48,7832
Non-polymers7698
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_565x,-y+1,-z+1/21
Buried area1680 Å2
ΔGint-109 kcal/mol
Surface area19580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.532, 85.532, 150.403
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-1132-

HOH

21B-1168-

HOH

DetailsThe natural state of the molecule is a monomer - there are two molecules of Cathepsin S 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: 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.: 1 / Source method: obtained synthetically / Formula: C25H31F3N4O6S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 591 / 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: 2.82 Å3/Da / Density % sol: 56.36 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20% PEG-8000, 0.4M Lithium Sulfate, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 278K

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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: Aug 28, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.55→84.2 Å / Num. all: 73915 / Num. obs: 73915 / % possible obs: 96.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.54 % / Rmerge(I) obs: 0.058 / Rsym value: 0.058 / Net I/σ(I): 21.5
Reflection shellResolution: 1.55→1.62 Å / Rmerge(I) obs: 0.509 / Mean I/σ(I) obs: 2.33 / Num. unique all: 6804 / Rsym value: 0.509 / % possible all: 86.3

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: RIGID BODY REFINEMENT
Starting model: 2F1G

2f1g


Resolution: 1.55→84.2 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.959 / SU B: 1.184 / SU ML: 0.043 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.067 / ESU R Free: 0.068 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: Hydrogens have been added in the riding positions. The density for chain A is too weak to reliably place the ligand (a low occupancy ligand). For chain B all atoms are present but density ...Details: Hydrogens have been added in the riding positions. The density for chain A is too weak to reliably place the ligand (a low occupancy ligand). For chain B all atoms are present but density for the 4-(TRIFLUOROMETHOXY)PHENYL AMINO group is largely missing. Those atoms have been labelled as occupancy 0.00 and are included on for comparison with 2HH5 structure.
RfactorNum. reflection% reflectionSelection details
Rfree0.17994 3951 5.1 %RANDOM
Rwork0.15543 ---
all0.15669 73915 --
obs0.15669 73915 96.19 %-
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: 12.839 Å2
Baniso -1Baniso -2Baniso -3
1--0.2 Å20 Å20 Å2
2---0.2 Å20 Å2
3---0.39 Å2
Refinement stepCycle: LAST / Resolution: 1.55→84.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3448 0 59 591 4098
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223635
X-RAY DIFFRACTIONr_bond_other_d0.0020.023073
X-RAY DIFFRACTIONr_angle_refined_deg1.4221.9734934
X-RAY DIFFRACTIONr_angle_other_deg0.76837203
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5425449
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.7424.268164
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.11215579
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9121516
X-RAY DIFFRACTIONr_chiral_restr0.0790.2496
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024092
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02764
X-RAY DIFFRACTIONr_nbd_refined0.2140.2840
X-RAY DIFFRACTIONr_nbd_other0.1940.23515
X-RAY DIFFRACTIONr_nbtor_refined0.1960.21879
X-RAY DIFFRACTIONr_nbtor_other0.0880.22026
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.2491
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.5990.220
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1950.251
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.160.243
X-RAY DIFFRACTIONr_mcbond_it1.35222777
X-RAY DIFFRACTIONr_mcbond_other0.2812919
X-RAY DIFFRACTIONr_mcangle_it1.60533511
X-RAY DIFFRACTIONr_scbond_it3.39651758
X-RAY DIFFRACTIONr_scangle_it4.70381418
LS refinement shellResolution: 1.554→1.594 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.26 207 -
Rwork0.226 4149 -
obs--73.82 %

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