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- PDB-8hfv: Crystal structure of CTSL in complex with K777 -

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Basic information

Entry
Database: PDB / ID: 8hfv
TitleCrystal structure of CTSL in complex with K777
ComponentsProcathepsin L
KeywordsHYDROLASE / inhibitor / antiviral / protease / ANTIVIRAL PROTEIN
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
MePip-Phe-HphVSPh / Chem-0IW / CACODYLATE ION / Procathepsin L
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsWang, H. / Shao, M. / Sun, L. / Yang, H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92169109 China
CitationJournal: Nat Commun / Year: 2023
Title: Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry.
Authors: Wang, H. / Yang, Q. / Liu, X. / Xu, Z. / Shao, M. / Li, D. / Duan, Y. / Tang, J. / Yu, X. / Zhang, Y. / Hao, A. / Wang, Y. / Chen, J. / Zhu, C. / Guddat, L. / Chen, H. / Zhang, L. / Chen, X. ...Authors: Wang, H. / Yang, Q. / Liu, X. / Xu, Z. / Shao, M. / Li, D. / Duan, Y. / Tang, J. / Yu, X. / Zhang, Y. / Hao, A. / Wang, Y. / Chen, J. / Zhu, C. / Guddat, L. / Chen, H. / Zhang, L. / Chen, X. / Jiang, B. / Sun, L. / Rao, Z. / Yang, H.
History
DepositionNov 12, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _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: Procathepsin L
B: Procathepsin L
C: Procathepsin L
D: Procathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,00144
Polymers96,7674
Non-polymers5,23440
Water11,458636
1
A: Procathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,50011
Polymers24,1921
Non-polymers1,30910
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1010 Å2
ΔGint-159 kcal/mol
Surface area9900 Å2
MethodPISA
2
B: Procathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,50011
Polymers24,1921
Non-polymers1,30910
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1010 Å2
ΔGint-159 kcal/mol
Surface area9430 Å2
MethodPISA
3
C: Procathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,50011
Polymers24,1921
Non-polymers1,30910
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1010 Å2
ΔGint-162 kcal/mol
Surface area9620 Å2
MethodPISA
4
D: Procathepsin L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,50011
Polymers24,1921
Non-polymers1,30910
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1010 Å2
ΔGint-159 kcal/mol
Surface area9860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)163.150, 38.300, 147.389
Angle α, β, γ (deg.)90.00, 103.97, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-558-

HOH

21C-527-

HOH

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Components

#1: Protein
Procathepsin L / Cathepesin L


Mass: 24191.701 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSL / Production host: Escherichia coli (E. coli) / References: UniProt: P07711
#2: Chemical...
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 28 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CAC / CACODYLATE ION / dimethylarsinate


Mass: 136.989 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: C2H6AsO2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-0IW / Nalpha-[(4-methylpiperazin-1-yl)carbonyl]-N-[(3S)-1-phenyl-5-(phenylsulfonyl)pentan-3-yl]-L-phenylalaninamide / APC-3316, bound form / 4-Methylpiperazine-1-carboxylic acid [1-[(3-benzenesulfonyl-1-phenethylallyl)carbamoyl]-2-phenylethyl]amide, bound form


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 576.749 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C32H40N4O4S / Feature type: SUBJECT OF INVESTIGATION / References: MePip-Phe-HphVSPh
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 636 / Source method: isolated from a natural source / Formula: H2O
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: 2.31 Å3/Da / Density % sol: 46.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 9% (v/v) 2-propanol, 90mM Sodium cacodylate/ Hydrochloric acid pH 6.5, 180mM Zinc acetate, 0.5% w/v n-dodecyl-N,N-dimethylamine-N-oxide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9785 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 1, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 2.1→47.68 Å / Num. obs: 52170 / % possible obs: 98.5 % / Redundancy: 5.21 % / CC1/2: 0.99 / Rmerge(I) obs: 0.189 / Rrim(I) all: 0.21 / Net I/σ(I): 7.47
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.1-2.220.75882160.6960.8441
2.22-2.370.5778350.8110.6331
2.37-2.560.44372670.8780.4911
2.56-2.810.32167540.9270.3561
2.81-3.140.21461860.9730.2381
3.14-3.620.12454330.9890.1371
3.62-4.430.07846770.9950.0871
4.43-6.240.07336780.9960.0821
6.24-47.680.06621240.9970.0741

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Processing

Software
NameVersionClassification
XDS2020-12-02data scaling
PHENIX1.20.1-4487-000refinement
XDS2020-12-02data reduction
PHENIX1.20.1-4487-000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MAJ

5maj


Resolution: 2.1→47.68 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.32 / Phase error: 23.53 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.242 1999 3.83 %
Rwork0.1967 --
obs0.1984 52147 98.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→47.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6701 0 232 636 7569
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077082
X-RAY DIFFRACTIONf_angle_d0.8399591
X-RAY DIFFRACTIONf_dihedral_angle_d19.6642553
X-RAY DIFFRACTIONf_chiral_restr0.048949
X-RAY DIFFRACTIONf_plane_restr0.0081261
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.150.32271380.26983451X-RAY DIFFRACTION95
2.15-2.210.31841410.25733550X-RAY DIFFRACTION100
2.21-2.270.2741400.24343491X-RAY DIFFRACTION97
2.27-2.340.27771400.22323546X-RAY DIFFRACTION100
2.34-2.430.26731410.22163516X-RAY DIFFRACTION97
2.43-2.520.25661410.21833564X-RAY DIFFRACTION99
2.52-2.640.29171430.21343551X-RAY DIFFRACTION98
2.64-2.780.21651410.20263574X-RAY DIFFRACTION98
2.78-2.950.23771450.20293611X-RAY DIFFRACTION99
2.95-3.180.25941420.20293579X-RAY DIFFRACTION99
3.18-3.50.24331450.17753622X-RAY DIFFRACTION99
3.5-4.010.19791450.15953625X-RAY DIFFRACTION100
4.01-5.050.19131460.15373684X-RAY DIFFRACTION99
5.05-47.680.23951510.19873784X-RAY DIFFRACTION98

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