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- PDB-8qkb: Crystal structure of human cathepsin L in complex with the vinyl ... -

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Basic information

Entry
Database: PDB / ID: 8qkb
TitleCrystal structure of human cathepsin L in complex with the vinyl sulfone inhibitor K777
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
Chem-D1R / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Procathepsin L
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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 14, 2023Deposition 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

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,34335
Polymers96,6474
Non-polymers4,69631
Water12,358686
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15440 Å2
ΔGint29 kcal/mol
Surface area33900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.990, 62.440, 67.750
Angle α, β, γ (deg.)105.407, 93.650, 115.528
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, 717 molecules

#2: Chemical
ChemComp-D1R / NALPHA-[(4-METHYLPIPERAZIN-1-YL)CARBONYL]-N-{(1S)-3-PHENYL-1-[2-(PHENYLSULFONYL)ETHYL]PROPYL}-L-PHENYLALANINAMIDE


Mass: 576.749 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C32H40N4O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


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


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


Mass: 150.173 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H14O4
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 686 / 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: 42.09 %
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: Sep 3, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.6→44.2 Å / Num. obs: 96403 / % possible obs: 91.7 % / Redundancy: 10.6 % / Biso Wilson estimate: 13.4 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.078 / Net I/σ(I): 21.91
Reflection shellResolution: 1.6→1.66 Å / Num. unique obs: 10046 / CC1/2: 0.974 / Rrim(I) all: 0.292 / % possible all: 91.8

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Processing

Software
NameVersionClassification
PHENIX1.18_3861refinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→44.19 Å / SU ML: 0.1294 / Cross valid method: FREE R-VALUE / σ(F): 2.01 / Phase error: 19.0749
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1867 1366 1.42 %
Rwork0.1572 95030 -
obs0.1576 96396 91.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 17.59 Å2
Refinement stepCycle: LAST / Resolution: 1.6→44.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6750 0 314 686 7750
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.017347
X-RAY DIFFRACTIONf_angle_d1.04339892
X-RAY DIFFRACTIONf_chiral_restr0.0593957
X-RAY DIFFRACTIONf_plane_restr0.01031302
X-RAY DIFFRACTIONf_dihedral_angle_d22.2672659
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.660.21841350.17269487X-RAY DIFFRACTION91.8
1.66-1.720.21051280.16669437X-RAY DIFFRACTION91.03
1.72-1.80.20261410.179337X-RAY DIFFRACTION90.61
1.8-1.90.19681230.16368920X-RAY DIFFRACTION85.81
1.9-2.020.18671400.16039745X-RAY DIFFRACTION94.32
2.02-2.170.20581430.169698X-RAY DIFFRACTION93.84
2.17-2.390.1941410.16079661X-RAY DIFFRACTION93.02
2.39-2.740.20541250.1659148X-RAY DIFFRACTION88.4
2.74-3.450.16041420.15979938X-RAY DIFFRACTION96.15
3.45-44.190.17241480.13989659X-RAY DIFFRACTION93.4

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