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- PDB-7zs7: Crystal structure of human cathepsin L with covalently bound calp... -

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Basic information

Entry
Database: PDB / ID: 7zs7
TitleCrystal structure of human cathepsin L with covalently bound calpain inhibitor VI
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 / Chem-JQO / DI(HYDROXYETHYL)ETHER / 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
DepositionMay 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 17, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2May 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

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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)99,22521
Polymers96,6474
Non-polymers2,57817
Water13,944774
1
A: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,6924
Polymers24,1621
Non-polymers5313
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7515
Polymers24,1621
Non-polymers5904
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7204
Polymers24,1621
Non-polymers5593
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0618
Polymers24,1621
Non-polymers8997
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.370, 62.560, 68.150
Angle α, β, γ (deg.)105.477, 93.430, 115.518
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 , 5 types, 791 molecules

#2: Chemical
ChemComp-JQO / (2S)-2-[(4-fluorophenyl)sulfonylamino]-3-methyl-N-[(2S)-4-methyl-1-oxidanyl-pentan-2-yl]butanamide


Mass: 374.471 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H27FN2O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#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.: 774 / 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: 2.16 Å3/Da / Density % sol: 42.96 %
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: Dec 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.59→44.4 Å / Num. obs: 101066 / % possible obs: 93 % / Redundancy: 18.4 % / Biso Wilson estimate: 17.28 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rrim(I) all: 0.323 / Net I/σ(I): 12.4
Reflection shellResolution: 1.59→1.63 Å / Num. unique obs: 7218 / CC1/2: 0.84 / Rrim(I) all: 1.677 / % possible all: 89.6

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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: 1.6→44.4 Å / SU ML: 0.1388 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 19.6058
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1877 1956 1.97 %
Rwork0.1561 97492 -
obs0.1568 99448 93.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.81 Å2
Refinement stepCycle: LAST / Resolution: 1.6→44.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6780 0 161 774 7715
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01277238
X-RAY DIFFRACTIONf_angle_d1.15799798
X-RAY DIFFRACTIONf_chiral_restr0.0754963
X-RAY DIFFRACTIONf_plane_restr0.00831300
X-RAY DIFFRACTIONf_dihedral_angle_d10.06031047
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.640.21411300.17397016X-RAY DIFFRACTION93.75
1.64-1.680.20591520.1676996X-RAY DIFFRACTION93.47
1.68-1.730.21871240.16766946X-RAY DIFFRACTION93.05
1.73-1.790.21741470.16636885X-RAY DIFFRACTION92.45
1.79-1.850.1841190.16896781X-RAY DIFFRACTION90.85
1.85-1.930.22581470.16266546X-RAY DIFFRACTION88.34
1.93-2.020.18611450.15517134X-RAY DIFFRACTION95.36
2.02-2.120.19821460.15037130X-RAY DIFFRACTION95.6
2.12-2.260.2041370.15387062X-RAY DIFFRACTION95.11
2.26-2.430.2131440.15947022X-RAY DIFFRACTION93.82
2.43-2.670.19111250.16476634X-RAY DIFFRACTION88.71
2.67-3.060.17331540.16227174X-RAY DIFFRACTION96.27
3.06-3.860.17971420.14937186X-RAY DIFFRACTION96.5
3.86-44.40.16651440.14626980X-RAY DIFFRACTION93.52

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