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- PDB-8b4f: Crystal structure of human cathepsin L forming a thiohemiacetal w... -

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Basic information

Entry
Database: PDB / ID: 8b4f
TitleCrystal structure of human cathepsin L forming a thiohemiacetal with N-Boc-2-aminoacetaldehyde
ComponentsCathepsin L
KeywordsHYDROLASE / cystein protease / drug target / lysosome / virus cell entry
Function / homology
Function and homology information


enkephalin processing / cathepsin L / CD4-positive, alpha-beta T cell lineage commitment / macrophage apoptotic process / chromaffin granule / elastin catabolic process / antigen processing and presentation of peptide antigen / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / cellular response to thyroid hormone stimulus ...enkephalin processing / cathepsin L / CD4-positive, alpha-beta T cell lineage commitment / macrophage apoptotic process / chromaffin granule / elastin catabolic process / antigen processing and presentation of peptide antigen / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / cellular response to thyroid hormone stimulus / Trafficking and processing of endosomal TLR / proteoglycan binding / zymogen activation / Assembly of collagen fibrils and other multimeric structures / antigen processing and presentation / protein autoprocessing / Collagen degradation / collagen catabolic process / fibronectin binding / serpin family protein binding / collagen binding / Attachment and Entry / Degradation of the extracellular matrix / receptor-mediated endocytosis of virus by host cell / multivesicular body / endocytic vesicle lumen / MHC class II antigen presentation / cysteine-type peptidase activity / lysosomal lumen / proteolysis involved in protein catabolic process / Endosomal/Vacuolar pathway / antigen processing and presentation of exogenous peptide antigen via MHC class II / : / histone binding / adaptive immune response / Attachment and Entry / lysosome / apical plasma membrane / fusion of virus membrane with host plasma membrane / cysteine-type endopeptidase activity / intracellular membrane-bounded organelle / fusion of virus membrane with host endosome membrane / symbiont entry into host cell / Golgi apparatus / proteolysis / extracellular space / extracellular exosome / extracellular region / nucleus / plasma membrane
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
~{tert}-butyl ~{N}-(2-hydroxyethyl)carbamate / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Procathepsin L
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsFalke, S. / Lieske, J. / Guenther, S. / Reinke, P.Y.A. / Ewert, W. / Loboda, J. / Karnicar, K. / Usenik, A. / Lindic, N. / Sekirnik, A. ...Falke, S. / Lieske, J. / Guenther, S. / Reinke, P.Y.A. / Ewert, W. / Loboda, J. / Karnicar, K. / Usenik, A. / Lindic, N. / Sekirnik, A. / Chapman, H.N. / Hinrichs, W. / Turk, D. / Meents, A.
Funding support Germany, Slovenia, 5items
OrganizationGrant numberCountry
Helmholtz AssociationFISCOV Germany
Helmholtz AssociationSFragX Germany
German Federal Ministry for Education and Research031B0405 Germany
Slovenian Research AgencyP1-0048 Slovenia
Slovenian Research AgencyIO-0048 Slovenia
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.
Authors: Falke, S. / Lieske, J. / Herrmann, A. / Loboda, J. / Karnicar, K. / Gunther, S. / Reinke, P.Y.A. / Ewert, W. / Usenik, A. / Lindic, N. / Sekirnik, A. / Dretnik, K. / Tsuge, H. / Turk, V. / ...Authors: Falke, S. / Lieske, J. / Herrmann, A. / Loboda, J. / Karnicar, K. / Gunther, S. / Reinke, P.Y.A. / Ewert, W. / Usenik, A. / Lindic, N. / Sekirnik, A. / Dretnik, K. / Tsuge, H. / Turk, V. / Chapman, H.N. / Hinrichs, W. / Ebert, G. / Turk, D. / Meents, A.
History
DepositionSep 20, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 22, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cathepsin L
B: Cathepsin L
C: Cathepsin L
D: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,19732
Polymers96,6474
Non-polymers2,55028
Water5,441302
1
A: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,8279
Polymers24,1621
Non-polymers6668
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,5535
Polymers24,1621
Non-polymers3914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,6827
Polymers24,1621
Non-polymers5216
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,13411
Polymers24,1621
Non-polymers97210
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10810 Å2
ΔGint36 kcal/mol
Surface area33870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.210, 62.260, 67.630
Angle α, β, γ (deg.)105.440, 93.413, 115.899
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Cathepsin L


Mass: 24161.676 Da / Num. of mol.: 4 / Mutation: T110A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSL, CTSL1 / Production host: Komagataella phaffii GS115 (fungus) / References: UniProt: P07711

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Non-polymers , 7 types, 330 molecules

#2: Chemical
ChemComp-OYU / ~{tert}-butyl ~{N}-(2-hydroxyethyl)carbamate


Mass: 161.199 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C7H15NO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 302 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.12 Å3/Da / Density % sol: 41.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4
Details: Mature cathepsin L at a concentration of 7 mg/ml was equilibrated against 27% w/v PEG 8000, 1 mM TCEP and 0.1 M sodium acetate at pH 4.0. Crystals, which grew at 293 K to final size after ...Details: Mature cathepsin L at a concentration of 7 mg/ml was equilibrated against 27% w/v PEG 8000, 1 mM TCEP and 0.1 M sodium acetate at pH 4.0. Crystals, which grew at 293 K to final size after approximately 3 days, were transferred to a compound soaking solution containing 22% w/v PEG 8000, 1 mM TCEP and 0.1 M sodium acetate at pH 4.0 as well as 5% v/v DMSO and 10% v/v PEG 400.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.033 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.9→49.42 Å / Num. obs: 117311 / % possible obs: 93.8 % / Redundancy: 5.6 % / Biso Wilson estimate: 21.85 Å2 / CC1/2: 0.995 / Rrim(I) all: 0.201 / Net I/σ(I): 7.14
Reflection shellResolution: 1.9→1.95 Å / Num. unique obs: 8921 / CC1/2: 0.68 / % possible all: 94.9

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Processing

Software
NameVersionClassification
PHENIX1.13-2998_9999refinement
XDSdata reduction
XSCALEdata scaling
PHENIX1.13-2998_9999phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3OF9

3of9


Resolution: 1.9→49.42 Å / SU ML: 0.1764 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 24.2778
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2099 1868 1.59 %
Rwork0.1775 115400 -
obs0.1781 117268 93.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.13 Å2
Refinement stepCycle: LAST / Resolution: 1.9→49.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6750 0 164 302 7216
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01067118
X-RAY DIFFRACTIONf_angle_d1.10079584
X-RAY DIFFRACTIONf_chiral_restr0.0573944
X-RAY DIFFRACTIONf_plane_restr0.01081269
X-RAY DIFFRACTIONf_dihedral_angle_d22.29492589
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.950.31861390.27088995X-RAY DIFFRACTION94.99
1.95-2.010.28751570.24488955X-RAY DIFFRACTION94.8
2.01-2.070.24911520.22648982X-RAY DIFFRACTION94.65
2.07-2.150.23031310.21248876X-RAY DIFFRACTION94.41
2.15-2.230.25361410.19618826X-RAY DIFFRACTION93.39
2.23-2.340.19671340.1918613X-RAY DIFFRACTION90.77
2.34-2.460.21251390.18487996X-RAY DIFFRACTION84.49
2.46-2.610.20631490.18029192X-RAY DIFFRACTION97.08
2.61-2.810.24161460.17159158X-RAY DIFFRACTION96.88
2.81-3.10.18321330.17839110X-RAY DIFFRACTION96.6
3.1-3.550.18971590.1659082X-RAY DIFFRACTION96.04
3.55-4.470.18371320.14358606X-RAY DIFFRACTION90.89
4.47-49.420.19151560.15839009X-RAY DIFFRACTION95.45

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