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- PDB-8pi3: Cathepsin S Y132D mutant in complex with NNPI-C10 inhibitor -

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Basic information

Entry
Database: PDB / ID: 8pi3
TitleCathepsin S Y132D mutant in complex with NNPI-C10 inhibitor
Components
  • Cathepsin S
  • NNPI-C10 inhibitor
KeywordsONCOPROTEIN / Protease / Inhibitor / Complex / Cathepsin
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 / : / DI(HYDROXYETHYL)ETHER / Cathepsin S
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.73 Å
AuthorsPetruzzella, A. / Lau, K. / Pojer, F. / Oricchio, E.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss Cancer LeagueKFS-5102-08-2020 Switzerland
CitationJournal: Nat.Chem.Biol. / Year: 2024
Title: Antibody-peptide conjugates deliver covalent inhibitors blocking oncogenic cathepsins.
Authors: Petruzzella, A. / Bruand, M. / Santamaria-Martinez, A. / Katanayeva, N. / Reymond, L. / Wehrle, S. / Georgeon, S. / Inel, D. / van Dalen, F.J. / Viertl, D. / Lau, K. / Pojer, F. / ...Authors: Petruzzella, A. / Bruand, M. / Santamaria-Martinez, A. / Katanayeva, N. / Reymond, L. / Wehrle, S. / Georgeon, S. / Inel, D. / van Dalen, F.J. / Viertl, D. / Lau, K. / Pojer, F. / Schottelius, M. / Zoete, V. / Verdoes, M. / Arber, C. / Correia, B.E. / Oricchio, E.
History
DepositionJun 21, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 5, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 12, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin S
B: NNPI-C10 inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,02222
Polymers26,5562
Non-polymers1,46620
Water1,17165
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4630 Å2
ΔGint-59 kcal/mol
Surface area10400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.706, 87.706, 69.436
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number94
Space group name H-MP42212
Space group name HallP4n2n
Components on special symmetry positions
IDModelComponents
11A-568-

PEG

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein Cathepsin S


Mass: 25345.420 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSS / Cell line (production host): ExpiCHO / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P25774, cathepsin S
#2: Protein/peptide NNPI-C10 inhibitor


Mass: 1210.500 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 7 types, 85 molecules

#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-CD / CADMIUM ION


Mass: 112.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cd
#7: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#8: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C4H10O3
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsCovalently-bound inhibitor for Cathepsin S
Has ligand of interestN

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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: 2.59 Å3/Da / Density % sol: 52.56 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2M ammonium sulfate, 0.01M Cadmium chloride hemi(pentahydrate), 0.1M Pipes pH 7, 15% PEG Smear Broad, 10% Ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.999859 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999859 Å / Relative weight: 1
ReflectionResolution: 1.73→43.85 Å / Num. obs: 54165 / % possible obs: 99.9 % / Redundancy: 8.49 % / Biso Wilson estimate: 29.04 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.12 / Net I/σ(I): 13.1
Reflection shellResolution: 1.73→1.82 Å / Redundancy: 8.1 % / Mean I/σ(I) obs: 0.74 / Num. unique obs: 8701 / CC1/2: 0.324 / Rrim(I) all: 2.71 / % possible all: 99.3

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Processing

Software
NameVersionClassification
PHENIXdev_5246refinement
PHASERphasing
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.73→43.85 Å / SU ML: 0.2776 / Cross valid method: FREE R-VALUE / σ(F): 1.91 / Phase error: 23.6341
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2059 2717 5.02 %
Rwork0.1761 51399 -
obs0.1776 54116 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 38.85 Å2
Refinement stepCycle: LAST / Resolution: 1.73→43.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1738 0 111 65 1914
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01241889
X-RAY DIFFRACTIONf_angle_d1.17542528
X-RAY DIFFRACTIONf_chiral_restr0.0587252
X-RAY DIFFRACTIONf_plane_restr0.0097326
X-RAY DIFFRACTIONf_dihedral_angle_d17.7191692
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.73-1.760.40621380.38812639X-RAY DIFFRACTION97.78
1.76-1.790.42211410.36832719X-RAY DIFFRACTION99.9
1.79-1.830.40121430.33622723X-RAY DIFFRACTION100
1.83-1.870.32281490.30862707X-RAY DIFFRACTION99.96
1.87-1.910.28681430.26742684X-RAY DIFFRACTION99.96
1.91-1.960.27461440.24382712X-RAY DIFFRACTION100
1.96-2.010.21461420.21532699X-RAY DIFFRACTION100
2.01-2.070.21651470.20122718X-RAY DIFFRACTION100
2.07-2.140.2161440.19332710X-RAY DIFFRACTION100
2.14-2.220.20531400.18542714X-RAY DIFFRACTION100
2.22-2.310.2131450.16472713X-RAY DIFFRACTION99.93
2.31-2.410.16941340.1642687X-RAY DIFFRACTION100
2.41-2.540.22131410.15262726X-RAY DIFFRACTION100
2.54-2.70.18781440.15692715X-RAY DIFFRACTION99.97
2.7-2.910.15541440.15492689X-RAY DIFFRACTION100
2.91-3.20.18191410.15042719X-RAY DIFFRACTION100
3.2-3.660.15911440.14222715X-RAY DIFFRACTION100
3.66-4.610.19151450.15032717X-RAY DIFFRACTION100
4.61-43.850.21781480.17962693X-RAY DIFFRACTION99.93
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)
13.38492286013-0.444683354078-2.596204435283.131264643993.959752430546.25804351934-0.003317466452790.05644434379270.71321211321-0.1754259937780.149843828278-0.40836867556-0.366294377697-0.020396945005-0.1940227589840.307643613988-0.0218575627849-0.06932759307080.2007198878940.0004636874962820.44018876625312.369795510626.205528327910.2379981148
25.700648847995.42824447485-2.272231081688.33778390718-3.581598160454.37134750951-0.0184777539704-0.0110538199669-0.3696021673980.187699019301-0.0731925587911-0.805382608813-0.01671138645150.1824160582950.08231131064790.1729280600570.0261342401054-0.03526852851320.171896460522-0.04603785884630.27449164685217.81574517538.536600809049.82134182234
32.64435390472-0.988112318950.5215388789515.58586678329-1.602558127564.204042013560.0420833548746-0.0365515633971-0.5408120593160.179878940631-0.0290320514553-0.5501690900170.4370028882150.344415483420.02507373836590.2315352028260.00539937090154-0.1055751073060.224583765737-0.009754244768120.49837574288524.43443012342.0225881099213.3180178037
46.532519629380.8786428904971.57916418260.3064048792770.8009687891662.303203916750.172313725431-0.242845091705-0.4416451681950.738866557698-0.133623884701-0.8949480044080.1335903751630.156432176428-0.004895607351640.4151074863360.00715696891332-0.2358287037740.2431556166920.005633554865160.50103139771422.8995156823.0702799959121.0352809607
56.84470226045-0.966695548083-0.33595922843.14651129278-1.261252018332.371834372350.03982394041990.427851508763-0.6492043355390.3129094031050.0966425467789-0.5716651427250.317301571580.22060783865-0.1107153498120.3031260135680.0474817547065-0.07952611811490.249297898909-0.1119716455740.53812081306424.7795361013-2.695404354829.52910228449
62.043302880380.0350192584341-0.05542978124092.924849306120.3261048392971.274192434750.0668939277382-0.2071157870620.1009322400240.448645895560.0131830798676-0.3520680553250.008093080480160.09262632175-0.08636915401440.333722400424-0.0551764712817-0.08871902010290.2334455914660.001280573885360.23881172224815.877985387612.532777144218.0078747049
76.80906330098-3.05548010495-1.805010130726.39208549894-2.573617245998.381962584720.0129411235728-0.696561394190.2910280353480.738768648360.0886516325410.495352827493-0.152506908013-0.536596311088-0.1445780990890.330101772958-0.1042753057650.08720456860250.175577515127-0.04880445236420.256728899029-1.1197044174210.742485601220.6653004477
86.19569676745-0.393881117367-0.6432948074967.739119951751.10315827454.129313517080.109940340990.1079934494960.2526778200290.127400658461-0.0996590656020.260489365412-0.152192939202-0.271786085458-0.001689838119030.189551718488-0.00888225977615-0.007481748399960.1999571135510.01936119303540.1581607675144.9083151558114.15189398811.9026956775
95.33420398070.839813258467-0.7238381982812.642371213660.5553877828742.710318529050.224482805901-0.5260845120040.3728522380740.43100464001-0.1994500061840.0213427034063-0.0836939624085-0.0599621269691-0.01581406137050.400805000797-0.0334687927596-0.02033101170530.199177442262-0.05161334295990.2406772376439.2369548570416.304549587719.9613968216
106.084873420135.863099244742.033201654475.674357568071.843762777071.15887280260.910379799257-1.07364262584-0.2751048962241.34619255795-0.535396407641-0.2856348171180.263749656393-0.642799981684-0.3766731472080.689556135112-0.0332708614883-0.0859716225260.4288338282290.0342857344590.36027552934511.37564450430.094588709790225.2449845311
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 113 through 124 )AA113 - 1241 - 12
22chain 'A' and (resid 125 through 156 )AA125 - 15613 - 44
33chain 'A' and (resid 157 through 175 )AA157 - 17545 - 63
44chain 'A' and (resid 176 through 194 )AA176 - 19464 - 82
55chain 'A' and (resid 195 through 214 )AA195 - 21483 - 102
66chain 'A' and (resid 215 through 261 )AA215 - 261103 - 149
77chain 'A' and (resid 262 through 277 )AA262 - 277150 - 165
88chain 'A' and (resid 278 through 308 )AA278 - 308166 - 196
99chain 'A' and (resid 309 through 331 )AA309 - 331197 - 219
1010chain 'B' and (resid 3 through 10 )BB3 - 103 - 10

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