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- PDB-6yyn: Structure of Cathepsin S in complex with Compound 14 -

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Basic information

Entry
Database: PDB / ID: 6yyn
TitleStructure of Cathepsin S in complex with Compound 14
ComponentsCathepsin S
KeywordsHYDROLASE / Cathepsin S / 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 peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Papain-like cysteine peptidase superfamily
Similarity search - Domain/homology
CITRATE ANION / Chem-Q1E / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.22 Å
AuthorsWagener, M. / Schade, M. / Merla, B. / Hars, U. / Kueckelhaus, S.Q.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors.
Authors: Schade, M. / Merla, B. / Lesch, B. / Wagener, M. / Timmermanns, S. / Pletinckx, K. / Hertrampf, T.
History
DepositionMay 5, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2022Group: Database references / Derived calculations
Category: atom_type / citation ...atom_type / citation / citation_author / database_2
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Cathepsin S
BBB: Cathepsin S
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,87412
Polymers50,2122
Non-polymers1,66110
Water8,611478
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2880 Å2
ΔGint-72 kcal/mol
Surface area19150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.671, 85.671, 150.922
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number91
Space group name H-MP4122
Components on special symmetry positions
IDModelComponents
11BBB-1005-

SO4

21AAA-1301-

HOH

31AAA-1344-

HOH

41BBB-1185-

HOH

51BBB-1253-

HOH

61BBB-1325-

HOH

Noncrystallographic symmetry (NCS)NCS domain: (Details: Chains AAA BBB) / NCS ensembles : (Details: Chains AAA BBB)

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Components

#1: Protein Cathepsin S


Mass: 25106.172 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSS / Production host: Escherichia coli (E. coli) / References: UniProt: P25774, cathepsin S
#2: Chemical ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H5O7
#3: Chemical ChemComp-Q1E / ~{N}-methyl-3-[4-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl]sulfonyl-propanamide


Mass: 353.400 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H19N7O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 478 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.76 Å3/Da / Density % sol: 55.39 %
Crystal growTemperature: 285 K / Method: vapor diffusion, hanging drop / pH: 4.8
Details: 0.1 M sodium citrate pH 4.8, 0.2 M ammonium sulfate, 17% w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.22→19.51 Å / Num. obs: 28281 / % possible obs: 99.4 % / Redundancy: 3.9 % / CC1/2: 0.994 / Rpim(I) all: 0.058 / Rrim(I) all: 0.118 / Net I/σ(I): 10.1
Reflection shellResolution: 2.22→2.34 Å / Redundancy: 3.8 % / Mean I/σ(I) obs: 2.5 / Num. unique obs: 4069 / CC1/2: 0.732 / Rpim(I) all: 0.344 / Rrim(I) all: 0.68 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: unpublished isomorphous structure

Resolution: 2.22→19.51 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.936 / SU B: 10.811 / SU ML: 0.142 / Cross valid method: FREE R-VALUE / ESU R: 0.22 / ESU R Free: 0.191
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.217 1436 5.081 %
Rwork0.1581 --
all0.161 --
obs-28263 99.005 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 33.279 Å2
Baniso -1Baniso -2Baniso -3
1-0.171 Å2-0 Å2-0 Å2
2--0.171 Å2-0 Å2
3----0.341 Å2
Refinement stepCycle: LAST / Resolution: 2.22→19.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3447 0 104 478 4029
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0133642
X-RAY DIFFRACTIONr_bond_other_d0.0090.0173153
X-RAY DIFFRACTIONr_angle_refined_deg1.7411.6554937
X-RAY DIFFRACTIONr_angle_other_deg1.6241.5987346
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9985440
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.12622.983181
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.20815570
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0931515
X-RAY DIFFRACTIONr_chiral_restr0.10.2432
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024092
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02781
X-RAY DIFFRACTIONr_nbd_refined0.1950.2846
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1880.23182
X-RAY DIFFRACTIONr_nbtor_refined0.1780.21807
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.21564
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2030.2330
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0150.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2170.225
X-RAY DIFFRACTIONr_nbd_other0.2570.263
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2010.234
X-RAY DIFFRACTIONr_mcbond_it1.3191.9831766
X-RAY DIFFRACTIONr_mcbond_other1.3191.9831767
X-RAY DIFFRACTIONr_mcangle_it2.1372.9632206
X-RAY DIFFRACTIONr_mcangle_other2.1372.9662206
X-RAY DIFFRACTIONr_scbond_it2.0342.3151876
X-RAY DIFFRACTIONr_scbond_other2.0372.3131870
X-RAY DIFFRACTIONr_scangle_it2.993.3922731
X-RAY DIFFRACTIONr_scangle_other2.993.3922732
X-RAY DIFFRACTIONr_lrange_it6.96325.594442
X-RAY DIFFRACTIONr_lrange_other6.86824.6424329
X-RAY DIFFRACTIONr_ncsr_local_group_10.1040.057138
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.22-2.2770.266870.2351959X-RAY DIFFRACTION99.659
2.277-2.3380.2561020.2131874X-RAY DIFFRACTION99.6973
2.338-2.4050.267950.2221824X-RAY DIFFRACTION99.8439
2.405-2.4780.263910.2151803X-RAY DIFFRACTION99.9472
2.478-2.5580.262910.1871732X-RAY DIFFRACTION99.9452
2.558-2.6460.211870.1661694X-RAY DIFFRACTION100
2.646-2.7440.294850.1771637X-RAY DIFFRACTION99.942
2.744-2.8540.268900.1651582X-RAY DIFFRACTION99.9402
2.854-2.9780.24670.1581519X-RAY DIFFRACTION99.937
2.978-3.120.216730.1551451X-RAY DIFFRACTION99.8689
3.12-3.2840.214880.1441374X-RAY DIFFRACTION99.7952
3.284-3.4770.199740.1581308X-RAY DIFFRACTION99.7834
3.477-3.7090.191860.1481228X-RAY DIFFRACTION99.924
3.709-3.9940.19620.1341163X-RAY DIFFRACTION99.837
3.994-4.3580.168530.1171094X-RAY DIFFRACTION98.8793
4.358-4.8430.186500.127988X-RAY DIFFRACTION98.017
4.843-5.5360.215570.134857X-RAY DIFFRACTION97.6496
5.536-6.6510.226440.158744X-RAY DIFFRACTION95.5152
6.651-8.9120.222320.145595X-RAY DIFFRACTION93.1649
8.912-19.510.161220.173401X-RAY DIFFRACTION89.4292
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.5802-0.09341.68071.36560.36492.9961-0.0927-0.14220.1054-0.00290.06050.0383-0.0476-0.00740.03220.07720.01740.00770.0287-0.01880.024621.76144.789813.4692
22.5395-0.09791.69851.88260.16213.1490.07680.1783-0.0379-0.1737-0.0017-0.1062-0.09230.2385-0.0750.08290.03010.02680.0993-0.02540.025811.814131.47923.0259
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLAAA0 - 2001
2X-RAY DIFFRACTION2ALLBBB-1 - 2001

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