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- PDB-8c3d: Sulfonated Calpeptin is a promising drug candidate against SARS-C... -

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Basic information

Entry
Database: PDB / ID: 8c3d
TitleSulfonated Calpeptin is a promising drug candidate against SARS-CoV-2 infections
Components
  • 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE
  • Cathepsin K
KeywordsHYDROLASE / cathepsin / inhibitor
Function / homology
Function and homology information


cathepsin K / negative regulation of cartilage development / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / thyroid hormone generation / Trafficking and processing of endosomal TLR / proteoglycan binding / Activation of Matrix Metalloproteinases / Collagen degradation / collagen catabolic process ...cathepsin K / negative regulation of cartilage development / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / thyroid hormone generation / Trafficking and processing of endosomal TLR / proteoglycan binding / Activation of Matrix Metalloproteinases / Collagen degradation / collagen catabolic process / fibronectin binding / extracellular matrix disassembly / bone resorption / mitophagy / collagen binding / Degradation of the extracellular matrix / MHC class II antigen presentation / cysteine-type peptidase activity / lysosomal lumen / proteolysis involved in protein catabolic process / lysosome / apical plasma membrane / external side of plasma membrane / serine-type endopeptidase activity / cysteine-type endopeptidase activity / intracellular membrane-bounded organelle / proteolysis / extracellular space / extracellular region / nucleoplasm
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
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 2 Å
AuthorsLoboda, J. / Karnicar, K. / Lindic, N. / Usenik, A. / Lieske, J. / Meents, A. / Guenther, S. / Reinke, P.Y.A. / Falke, S. / Ewert, W. / Turk, D.
Funding support Slovenia, 1items
OrganizationGrant numberCountry
Slovenian Research Agency Slovenia
CitationJournal: Commun Biol / Year: 2023
Title: Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections.
Authors: Reinke, P.Y.A. / de Souza, E.E. / Gunther, S. / Falke, S. / Lieske, J. / Ewert, W. / Loboda, J. / Herrmann, A. / Rahmani Mashhour, A. / Karnicar, K. / Usenik, A. / Lindic, N. / Sekirnik, A. ...Authors: Reinke, P.Y.A. / de Souza, E.E. / Gunther, S. / Falke, S. / Lieske, J. / Ewert, W. / Loboda, J. / Herrmann, A. / Rahmani Mashhour, A. / Karnicar, K. / Usenik, A. / Lindic, N. / Sekirnik, A. / Botosso, V.F. / Santelli, G.M.M. / Kapronezai, J. / de Araujo, M.V. / Silva-Pereira, T.T. / Filho, A.F.S. / Tavares, M.S. / Florez-Alvarez, L. / de Oliveira, D.B.L. / Durigon, E.L. / Giaretta, P.R. / Heinemann, M.B. / Hauser, M. / Seychell, B. / Bohler, H. / Rut, W. / Drag, M. / Beck, T. / Cox, R. / Chapman, H.N. / Betzel, C. / Brehm, W. / Hinrichs, W. / Ebert, G. / Latham, S.L. / Guimaraes, A.M.S. / Turk, D. / Wrenger, C. / Meents, A.
History
DepositionDec 23, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 2.0Nov 1, 2023Group: Atomic model / Database references / Category: atom_site / citation / citation_author
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _citation.country / _citation.journal_abbrev / _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
Revision 3.0Nov 15, 2023Group: Atomic model / Data collection / Category: atom_site / chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin K
LIG: 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,9263
Polymers23,8862
Non-polymers401
Water4,270237
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area780 Å2
ΔGint-14 kcal/mol
Surface area9920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.63, 41.62, 65.66
Angle α, β, γ (deg.)90.00, 121.01, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-301-

CA

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Components

#1: Protein Cathepsin K / Cathepsin O / Cathepsin O2 / Cathepsin X


Mass: 23523.480 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSK, CTSO, CTSO2 / Production host: Komagataella pastoris (fungus) / References: UniProt: P43235, cathepsin K
#2: Protein/peptide 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE


Type: Peptide-like / Class: Inhibitor / Mass: 362.464 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: BIRD: PRD_002387
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 237 / 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: 2.32 Å3/Da / Density % sol: 46.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 30 % PEG-3350, 0.2 M CaCL2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 16, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 14939 / % possible obs: 98.9 % / Redundancy: 5.89 % / CC1/2: 0.997 / Net I/σ(I): 23.32
Reflection shellResolution: 2→2.12 Å / Num. unique obs: 2322 / CC1/2: 0.961

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Processing

Software
NameClassification
MAINrefinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: SAD
Starting model: 6QBS

6qbs


Resolution: 2→34.94 Å / Cor.coef. Fo:Fc: 0.0947 / Cor.coef. Fo:Fc free: 0.0493 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 21.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2268 14932 100 %NONE
Rwork0.1959 14932 --
all0.5248 ---
obs0.1959 14932 100 %-
Solvent computationSolvent model: MASK FLAT BULK SOLVENT MODEL / Bsol: 15.39 Å2 / ksol: 0.32 e/Å3
Displacement parametersBiso max: 52.54 Å2 / Biso mean: 11.37 Å2 / Biso min: 1 Å2
Baniso -1Baniso -2Baniso -3
1-0.172 Å20 Å2-0.601 Å2
2---0.309 Å20 Å2
3---0.137 Å2
Refinement stepCycle: LAST / Resolution: 2→34.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1649 0 27 237 1913
LS refinement shellResolution: 2→2.03 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2405 682 100 %
Rwork0.1887 682 -
all-682 -
obs-682 1 %

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