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- PDB-6yyp: Structure of Cathepsin S in complex with Compound 2 -

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Basic information

Entry
Database: PDB / ID: 6yyp
TitleStructure of Cathepsin S in complex with Compound 2
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
ACETATE ION / MALONIC ACID / Chem-Q1H / SUCCINIC ACID / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.05 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)51,20612
Polymers50,2442
Non-polymers96210
Water7,999444
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3100 Å2
ΔGint-10 kcal/mol
Surface area19100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.689, 118.689, 205.586
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11BBB-1002-

MLA

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Components

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Protein , 1 types, 2 molecules AAABBB

#1: Protein Cathepsin S


Mass: 25122.172 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

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Non-polymers , 5 types, 454 molecules

#2: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-Q1H / 1-(furan-2-ylmethyl)-5-(trifluoromethyl)benzimidazol-2-amine


Mass: 281.233 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H10F3N3O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SIN / SUCCINIC ACID


Mass: 118.088 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O4
#5: Chemical ChemComp-MLA / MALONIC ACID / DICARBOXYLIC ACID C3 / PROPANEDIOLIC ACID / METHANEDICARBOXYLIC ACID


Mass: 104.061 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H4O4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 444 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.77 Å3/Da / Density % sol: 55.65 %
Crystal growTemperature: 285 K / Method: vapor diffusion, hanging drop / pH: 6.8 / Details: 54% v/v tacsimate pH 6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 30, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.05→30 Å / Num. obs: 34644 / % possible obs: 98.7 % / Redundancy: 3.9 % / CC1/2: 0.99 / Rpim(I) all: 0.066 / Rrim(I) all: 0.135 / Net I/σ(I): 7.4
Reflection shellResolution: 2.05→2.16 Å / Redundancy: 4 % / Mean I/σ(I) obs: 2.5 / Num. unique obs: 5079 / CC1/2: 0.632 / Rpim(I) all: 0.32 / Rrim(I) all: 0.663 / % possible all: 99.4

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Processing

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

Resolution: 2.05→29.691 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.953 / SU B: 7.803 / SU ML: 0.104 / Cross valid method: FREE R-VALUE / ESU R: 0.144 / ESU R Free: 0.137
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1877 1708 4.93 %
Rwork0.1415 --
all0.144 --
obs-34643 98.089 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 31.859 Å2
Baniso -1Baniso -2Baniso -3
1-0.301 Å20.15 Å2-0 Å2
2--0.301 Å2-0 Å2
3----0.975 Å2
Refinement stepCycle: LAST / Resolution: 2.05→29.691 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3448 0 66 444 3958
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0133642
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173174
X-RAY DIFFRACTIONr_angle_refined_deg1.731.6514925
X-RAY DIFFRACTIONr_angle_other_deg1.4531.5857394
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7935448
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.11122.989184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.49115576
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7521515
X-RAY DIFFRACTIONr_chiral_restr0.0870.2431
X-RAY DIFFRACTIONr_gen_planes_refined0.010.024154
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02789
X-RAY DIFFRACTIONr_nbd_refined0.2110.2720
X-RAY DIFFRACTIONr_symmetry_nbd_other0.180.23161
X-RAY DIFFRACTIONr_nbtor_refined0.1770.21789
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.21625
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1930.2327
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.080.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2480.220
X-RAY DIFFRACTIONr_nbd_other0.2170.275
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.3790.233
X-RAY DIFFRACTIONr_mcbond_it1.3272.0781781
X-RAY DIFFRACTIONr_mcbond_other1.3022.071776
X-RAY DIFFRACTIONr_mcangle_it1.9973.0922216
X-RAY DIFFRACTIONr_mcangle_other1.9963.0942217
X-RAY DIFFRACTIONr_scbond_it2.2882.4551861
X-RAY DIFFRACTIONr_scbond_other2.2872.4571862
X-RAY DIFFRACTIONr_scangle_it3.6033.5542705
X-RAY DIFFRACTIONr_scangle_other3.6023.5562706
X-RAY DIFFRACTIONr_lrange_it6.68226.5554316
X-RAY DIFFRACTIONr_lrange_other6.58825.5014206
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.1010.259990.2412461X-RAY DIFFRACTION99.1864
2.101-2.1590.2481390.2192379X-RAY DIFFRACTION99.212
2.159-2.2210.2331270.1972279X-RAY DIFFRACTION98.8903
2.221-2.290.2341160.1932238X-RAY DIFFRACTION98.9491
2.29-2.3650.211160.1762188X-RAY DIFFRACTION98.757
2.365-2.4480.2271330.1642052X-RAY DIFFRACTION99.093
2.448-2.540.205960.1472037X-RAY DIFFRACTION98.9791
2.54-2.6430.199980.1391979X-RAY DIFFRACTION98.6698
2.643-2.7610.209850.1521873X-RAY DIFFRACTION98.4414
2.761-2.8960.1961050.1511764X-RAY DIFFRACTION98.0073
2.896-3.0520.162900.1351692X-RAY DIFFRACTION97.9121
3.052-3.2370.179820.1281620X-RAY DIFFRACTION98.2112
3.237-3.460.177690.1211529X-RAY DIFFRACTION97.7968
3.46-3.7370.135750.1121393X-RAY DIFFRACTION96.6425
3.737-4.0930.151590.11301X-RAY DIFFRACTION97.2123
4.093-4.5750.15650.0981171X-RAY DIFFRACTION97.3228
4.575-5.280.152560.1171042X-RAY DIFFRACTION96.3158
5.28-6.4620.211380.154879X-RAY DIFFRACTION94.8294
6.462-9.1160.195400.135675X-RAY DIFFRACTION94.3272
9.116-29.6910.243200.178383X-RAY DIFFRACTION89.1593
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)
11.9292-0.11070.92131.347-0.00943.4334-0.00630.0475-0.0011-0.02960.09830.0307-0.11280.1026-0.0920.0326-0.01510.04110.0182-0.00950.0637-41.209243.27159.2293
22.34930.46380.45241.48930.63431.7599-0.0408-0.09980.04880.03850.04040.06050.05260.00050.00040.03320.02030.00910.0294-0.00190.0102-16.621315.727114.1709
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLAAA0 - 2001
2X-RAY DIFFRACTION2ALLBBB0 - 1007

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