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- PDB-8a5b: Crystal structure of human cathepsin L in complex with covalently... -

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Basic information

Entry
Database: PDB / ID: 8a5b
TitleCrystal structure of human cathepsin L in complex with covalently bound MG-101
Components
  • Calpain Inhibitor I
  • Cathepsin 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
Inhibitor, Peptide-like / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Procathepsin L
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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
DepositionJun 14, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Category: atom_site / chem_comp_atom / chem_comp_bond / Item: _atom_site.auth_atom_id / _atom_site.label_atom_id
Revision 2.1Feb 7, 2024Group: Refinement description / Category: pdbx_initial_refinement_model
Revision 2.2May 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 2.3May 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

Downloads & links

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Assembly

Deposited unit
A: Cathepsin L
B: Cathepsin L
C: Cathepsin L
D: Cathepsin L
E: Calpain Inhibitor I
F: Calpain Inhibitor I
G: Calpain Inhibitor I
H: Calpain Inhibitor I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,74916
Polymers98,1898
Non-polymers5608
Water4,468248
1
A: Cathepsin L
E: Calpain Inhibitor I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7204
Polymers24,5472
Non-polymers1732
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1340 Å2
ΔGint-13 kcal/mol
Surface area10240 Å2
MethodPISA
2
B: Cathepsin L
F: Calpain Inhibitor I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,5934
Polymers24,5472
Non-polymers462
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1110 Å2
ΔGint-27 kcal/mol
Surface area10000 Å2
MethodPISA
3
C: Cathepsin L
G: Calpain Inhibitor I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,6533
Polymers24,5472
Non-polymers1061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint-9 kcal/mol
Surface area9850 Å2
MethodPISA
4
D: Cathepsin L
H: Calpain Inhibitor I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7825
Polymers24,5472
Non-polymers2353
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1290 Å2
ΔGint-16 kcal/mol
Surface area9710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.240, 62.200, 67.240
Angle α, β, γ (deg.)105.349, 93.245, 115.807
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 / Protein/peptide , 2 types, 8 molecules ABCDEFGH

#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
#2: Protein/peptide
Calpain Inhibitor I / MG-101


Type: Peptide-like / Class: Inhibitor / Mass: 385.542 Da / Num. of mol.: 4 / Source method: obtained synthetically / Details: Calpain I inhibitor / Source: (synth.) synthetic construct (others) / References: Inhibitor, Peptide-like

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Non-polymers , 4 types, 256 molecules

#3: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 248 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound details2-ACETYLAMINO-4-METHYL-PENTANOIC ACID [1-(1-FORMYL-PENTYLCARBAMOYL)-3-METHYL-BUTYL]-AMIDE
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: 2.11 Å3/Da / Density % sol: 41.65 %
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: Nov 12, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.8→49.25 Å / Num. obs: 73714 / % possible obs: 99.3 % / Redundancy: 17.3 % / Biso Wilson estimate: 24.43 Å2 / CC1/2: 0.97 / Net I/σ(I): 7.59
Reflection shellResolution: 1.8→1.87 Å / Num. unique obs: 7195 / CC1/2: 0.72

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Processing

Software
NameVersionClassification
PHENIX1.18_3861refinement
XDSdata reduction
XSCALEdata scaling
PHENIX1.13-2998_9999phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3OF9

3of9


Resolution: 1.8→49.25 Å / SU ML: 0.2212 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 23.8363
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2245 1338 1.84 %
Rwork0.1784 71385 -
obs0.1793 72723 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.89 Å2
Refinement stepCycle: LAST / Resolution: 1.8→49.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6750 0 143 248 7141
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01077133
X-RAY DIFFRACTIONf_angle_d1.09299636
X-RAY DIFFRACTIONf_chiral_restr0.0612962
X-RAY DIFFRACTIONf_plane_restr0.00791280
X-RAY DIFFRACTIONf_dihedral_angle_d16.79871053
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.860.26551290.2237130X-RAY DIFFRACTION99.02
1.86-1.940.32431330.22017082X-RAY DIFFRACTION98.88
1.94-2.030.28691430.19817142X-RAY DIFFRACTION99.59
2.03-2.130.23841230.19377182X-RAY DIFFRACTION99.73
2.13-2.270.28131360.19287161X-RAY DIFFRACTION99.74
2.27-2.440.24081420.18227133X-RAY DIFFRACTION99.81
2.44-2.690.23111250.19227100X-RAY DIFFRACTION98.57
2.69-3.080.22921390.18467184X-RAY DIFFRACTION99.99
3.08-3.880.21291290.17277183X-RAY DIFFRACTION99.95
3.88-49.250.17721390.15077088X-RAY DIFFRACTION98.77

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