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- PDB-8ofa: Crystal structure of human cathepsin L interacting with tosyl phe... -

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Basic information

Entry
Database: PDB / ID: 8ofa
TitleCrystal structure of human cathepsin L interacting with tosyl phenylalanyl chloromethyl ketone (TPCK)
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 / zymogen activation / proteoglycan binding / Assembly of collagen fibrils and other multimeric structures / antigen processing and presentation / cysteine-type endopeptidase activator activity involved in apoptotic process / fibronectin binding / protein autoprocessing / Collagen degradation / collagen catabolic process / serpin family protein binding / cysteine-type peptidase activity / Attachment and Entry / endocytic vesicle lumen / collagen binding / MHC class II antigen presentation / Degradation of the extracellular matrix / multivesicular body / lysosomal lumen / proteolysis involved in protein catabolic process / Endosomal/Vacuolar pathway / positive regulation of apoptotic signaling pathway / antigen processing and presentation of exogenous peptide antigen via MHC class II / histone binding / collagen-containing extracellular matrix / adaptive immune response / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / lysosome / symbiont entry into host cell / immune response / 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 / 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
ACETATE ION / DI(HYDROXYETHYL)ETHER / 1-METHOXY-2-[2-(2-METHOXY-ETHOXY]-ETHANE / TRIETHYLENE GLYCOL / Chem-TQ8 / Chem-VLF / 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. / Ewert, W. / Reinke, P.Y.A. / Loboda, J. / Karnicar, K. / Usenik, A. / Lindic, N. / Sekirnik, A. ...Falke, S. / Lieske, J. / Guenther, S. / Ewert, W. / Reinke, P.Y.A. / 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
DepositionMar 14, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 29, 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

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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)101,28938
Polymers96,6474
Non-polymers4,64234
Water10,016556
1
A: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,68411
Polymers24,1621
Non-polymers1,52210
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,8977
Polymers24,1621
Non-polymers7356
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0508
Polymers24,1621
Non-polymers8897
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,65812
Polymers24,1621
Non-polymers1,49611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.960, 62.730, 67.370
Angle α, β, γ (deg.)105.065, 94.087, 115.543
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 , 9 types, 590 molecules

#2: Chemical
ChemComp-TQ8 / N-[(2S)-4-chloro-3-oxo-1-phenyl-butan-2-yl]-4-methyl-benzenesulfonamide / CAS329306


Mass: 351.848 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H18ClNO3S / Feature type: SUBJECT OF INVESTIGATION / Comment: protease inhibitor*YM
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H14O4
#7: Chemical ChemComp-PG5 / 1-METHOXY-2-[2-(2-METHOXY-ETHOXY]-ETHANE


Mass: 178.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O4
#8: Chemical ChemComp-VLF / 4-methyl-~{N}-[(2~{S})-4-oxidanyl-3-oxidanylidene-1-phenyl-butan-2-yl]benzenesulfonamide


Mass: 333.402 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H19NO4S / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 556 / 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: 2.12 Å3/Da / Density % sol: 42.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion
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→49.62 Å / Num. obs: 114947 / % possible obs: 91.7 % / Redundancy: 3.8 % / Biso Wilson estimate: 18.04 Å2 / CC1/2: 0.996 / Rrim(I) all: 0.123 / Net I/σ(I): 11.27
Reflection shellResolution: 1.9→1.95 Å / Mean I/σ(I) obs: 3.57 / Num. unique obs: 8667 / Rrim(I) all: 0.479 / % possible all: 92.4

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Processing

Software
NameVersionClassification
PHENIX1.18_3861refinement
XDSdata reduction
XSCALEdata scaling
PHENIX1.13-2998_9999phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→49.62 Å / SU ML: 0.192 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 22.7048
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2171 1900 1.65 %
Rwork0.1751 112994 -
obs0.1758 114894 91.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.11 Å2
Refinement stepCycle: LAST / Resolution: 1.9→49.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6658 0 293 556 7507
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00997211
X-RAY DIFFRACTIONf_angle_d1.00789708
X-RAY DIFFRACTIONf_chiral_restr0.0542936
X-RAY DIFFRACTIONf_plane_restr0.01011276
X-RAY DIFFRACTIONf_dihedral_angle_d22.19632656
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.950.2581500.22468123X-RAY DIFFRACTION92.31
1.95-20.29991400.20698088X-RAY DIFFRACTION92.39
2-2.060.22471340.20488123X-RAY DIFFRACTION92.3
2.06-2.130.26081420.19868118X-RAY DIFFRACTION92.17
2.13-2.20.24471140.19498052X-RAY DIFFRACTION90.77
2.2-2.290.22641420.19067824X-RAY DIFFRACTION89.53
2.29-2.390.28031300.18667325X-RAY DIFFRACTION83.33
2.39-2.520.22461180.17667895X-RAY DIFFRACTION89.73
2.52-2.680.2511390.18228386X-RAY DIFFRACTION95.1
2.68-2.880.23051540.17718369X-RAY DIFFRACTION95.76
2.88-3.170.21831370.18078421X-RAY DIFFRACTION95.13
3.17-3.630.22431380.16358204X-RAY DIFFRACTION93.75
3.63-4.580.13731180.14297673X-RAY DIFFRACTION86.66
4.58-49.620.18511440.1588393X-RAY DIFFRACTION95.6

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