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- PDB-3of8: Structural Basis for Reversible and Irreversible Inhibition of Hu... -

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Basic information

Entry
Database: PDB / ID: 3of8
TitleStructural Basis for Reversible and Irreversible Inhibition of Human Cathepsin L by their Respective Dipeptidyl Glyoxal and Diazomethylketone Inhibitors
ComponentsCathepsin L1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR complex
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 / zymogen activation / Trafficking and processing of endosomal TLR / proteoglycan binding / Assembly of collagen fibrils and other multimeric structures / cysteine-type endopeptidase activator activity involved in apoptotic process / protein autoprocessing / fibronectin binding / Collagen degradation / antigen processing and presentation / collagen catabolic process / serpin family protein binding / Attachment and Entry / cysteine-type peptidase activity / 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 / positive regulation of apoptotic signaling pathway / Endosomal/Vacuolar 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 proteinases / Cysteine peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Cathepsin B; Chain A / Papain-like cysteine peptidase superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
NALPHA-[(BENZYLOXY)CARBONYL]-N-[(2S)-1-(4-TERT-BUTOXYPHENYL)-4-HYDROXY-3-OXOBUTAN-2-YL]-L-PHENYLALANINAMIDE / Chem-I0Y / Procathepsin L
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsShenoy, R.T. / Sivaraman, J.
CitationJournal: J.Struct.Biol. / Year: 2011
Title: Structural basis for reversible and irreversible inhibition of human cathepsin L by their respective dipeptidyl glyoxal and diazomethylketone inhibitors.
Authors: Shenoy, R.T. / Sivaraman, J.
History
DepositionAug 14, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 8, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Nov 8, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software
Revision 1.4Jul 17, 2019Group: Data collection / Derived calculations / Refinement description
Category: software / struct_conn
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.location / _software.name / _software.type / _software.version / _struct_conn.pdbx_leaving_atom_flag
Revision 1.5Sep 6, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin L1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,8532
Polymers24,3211
Non-polymers5331
Water84747
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.318, 85.318, 50.018
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#1: Protein Cathepsin L1 / / Major excreted protein / MEP / Cathepsin L1 heavy chain / Cathepsin L1 light chain


Mass: 24320.814 Da / Num. of mol.: 1 / Fragment: residues 113-333
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSL1, CTSL / Plasmid: pPIC9 / Production host: Pichia pastoris (fungus) / References: UniProt: P07711, cathepsin L
#2: Chemical ChemComp-I0Y / Nalpha-[(benzyloxy)carbonyl]-N-[(2S)-1-(4-tert-butoxyphenyl)-4-hydroxy-3-oxobutan-2-yl]-L-phenylalaninamide / Z-Phe-Tyr(OBut)-COCHO


Type: peptide-like, Peptide-like / Class: Enzyme inhibitor / Mass: 532.627 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H36N2O6
References: NALPHA-[(BENZYLOXY)CARBONYL]-N-[(2S)-1-(4-TERT-BUTOXYPHENYL)-4-HYDROXY-3-OXOBUTAN-2-YL]-L-PHENYLALANINAMIDE
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 47 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE INHIBITOR Z-PHE-TYR (OBUT)-COCHO IS AN ALDEHYDE. AS IT GETS COVALENTLY ATTACHED TO THE CYS25 ...THE INHIBITOR Z-PHE-TYR (OBUT)-COCHO IS AN ALDEHYDE. AS IT GETS COVALENTLY ATTACHED TO THE CYS25 THIOL GROUP, IT FORMS A THIOHEMIACETAL

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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: 2.15 Å3/Da / Density % sol: 42.91 %
Crystal growTemperature: 298 K / pH: 5
Details: 20 mM Sodium acetate pH 5.1, 100 mM NaCl, and 1mM EDTA, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.5418
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 28, 2008
RadiationScattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / % possible obs: 86 % / Observed criterion σ(I): 1

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Processing

Software
NameVersionClassificationNB
PHENIX1.6_289refinement
SCALEPACKdata scaling
MOLREPphasing
CNSrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data reduction
HKL-2000data scaling
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1CS8

1cs8


Resolution: 2.2→42.659 Å / Occupancy max: 1 / Occupancy min: 0.5 / SU ML: 0.33 / σ(F): 1.34 / Phase error: 25.7 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.253 485 4.79 %
Rwork0.1939 --
obs0.1966 10120 94.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 40.071 Å2 / ksol: 0.413 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--4.5343 Å20 Å20 Å2
2---4.5343 Å2-0 Å2
3---9.0685 Å2
Refinement stepCycle: LAST / Resolution: 2.2→42.659 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1706 0 39 47 1792
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081793
X-RAY DIFFRACTIONf_angle_d1.2062420
X-RAY DIFFRACTIONf_dihedral_angle_d18.195649
X-RAY DIFFRACTIONf_chiral_restr0.074238
X-RAY DIFFRACTIONf_plane_restr0.009322
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.51860.30121400.21422866X-RAY DIFFRACTION85
2.5186-3.1730.25251680.1843347X-RAY DIFFRACTION100
3.173-42.6670.23981770.1923422X-RAY DIFFRACTION100
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1CNS_TOPPAR:protein_rep.param
X-RAY DIFFRACTION2CNS_TOPPAR:water_rep.param
X-RAY DIFFRACTION3inh5.par

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