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- PDB-1mhw: Design of non-covalent inhibitors of human cathepsin L. From the ... -

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Basic information

Entry
Database: PDB / ID: 1mhw
TitleDesign of non-covalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides
Components
  • (Cathepsin L) x 2
  • 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide
KeywordsHYDROLASE/HYDROLASE INHIBITOR / CATHEPSIN L / CYSTEINE PROTEASE / 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 / 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
Cysteine proteinases. Chain C / 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. ...Cysteine proteinases. Chain C / 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 / OB fold (Dihydrolipoamide Acetyltransferase, E2P) / Alpha-Beta Complex / Beta Barrel / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
4-biphenylacetyl-CYS-(D)ARG-TYR-N-(2-phenylethyl) amide / Procathepsin L
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsChowdhury, S. / Sivaraman, J. / Wang, J. / Devanathan, G. / Lachance, P. / Qi, H. / Menard, R. / Lefebvre, J. / Konishi, Y. / Cygler, M. ...Chowdhury, S. / Sivaraman, J. / Wang, J. / Devanathan, G. / Lachance, P. / Qi, H. / Menard, R. / Lefebvre, J. / Konishi, Y. / Cygler, M. / Sulea, T. / Purisima, E.O.
CitationJournal: J.Med.Chem. / Year: 2002
Title: Design of non-covalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides
Authors: Chowdhury, S. / Sivaraman, J. / Wang, J. / Devanathan, G. / Lachance, P. / Qi, H. / Menard, R. / Lefebvre, J. / Konishi, Y. / Cygler, M. / Sulea, T. / Purisima, E.O.
History
DepositionAug 21, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Nov 19, 2014Group: Non-polymer description
Revision 1.5Oct 11, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cathepsin L
C: Cathepsin L
B: Cathepsin L
D: Cathepsin L
E: 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide
F: 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide
G: 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide
H: 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide


Theoretical massNumber of molelcules
Total (without water)50,7818
Polymers50,7818
Non-polymers00
Water9,458525
1
A: Cathepsin L
C: Cathepsin L
F: 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide
G: 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide


Theoretical massNumber of molelcules
Total (without water)25,3904
Polymers25,3904
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin L
D: Cathepsin L
E: 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide
H: 4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide


Theoretical massNumber of molelcules
Total (without water)25,3904
Polymers25,3904
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.522, 58.632, 151.445
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Cathepsin L / Major excreted protein / MEP


Mass: 19127.020 Da / Num. of mol.: 2 / Fragment: HEAVY CHAIN (residues 114-288)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Pichia pastoris (fungus) / References: UniProt: P07711, cathepsin L
#2: Protein/peptide Cathepsin L / Major excreted protein / MEP


Mass: 4783.409 Da / Num. of mol.: 2 / Fragment: LIGHT CHAIN (residues 292-333)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Pichia pastoris (fungus) / References: UniProt: P07711, cathepsin L
#3: Protein/peptide
4-biphenylacetyl-Cys-(D)Arg-Tyr-N-(2-phenylethyl) amide


Type: Peptide-like / Class: Inhibitor / Mass: 739.927 Da / Num. of mol.: 4 / Source method: obtained synthetically
References: 4-biphenylacetyl-CYS-(D)ARG-TYR-N-(2-phenylethyl) amide
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 525 / Source method: isolated from a natural source / Formula: H2O

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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: 2.25 Å3/Da / Density % sol: 45.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.2
Details: PEG 8K, Na Citrate, LiSo4, Isoproponal, pH 4.2, VAPOR DIFFUSION, HANGING DROP, temperature 293K
Crystal grow
*PLUS
Temperature: 18 ℃
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
18.7 mg/mlprotein1drop
218 %(w/v)PEG80001reservoir
3200 mMsodium citrate1reservoirpH4.2
4200 mM1reservoirLi2SO4
58 %2-propanol1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IIC / Detector: IMAGE PLATE / Date: Feb 10, 2002
RadiationMonochromator: Graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 137661 / Num. obs: 134326 / % possible obs: 92.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4 % / Rsym value: 0.049 / Net I/σ(I): 18.9
Reflection shellResolution: 1.9→1.97 Å / % possible all: 58
Reflection
*PLUS
Lowest resolution: 50 Å / Num. obs: 34166 / Num. measured all: 134326 / Rmerge(I) obs: 0.049

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
AMoREphasing
CNS1refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1CJL

1cjl


Resolution: 1.9→45 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2295 2391 -Random
Rwork0.1846 ---
all-34139 --
obs-34139 92.2 %-
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: LAST / Resolution: 1.9→45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3482 0 0 525 4007
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.0098
X-RAY DIFFRACTIONc_angle_deg1.26648
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2water_rep.param
X-RAY DIFFRACTION3bpa_inh.par
Refinement
*PLUS
Lowest resolution: 30 Å / Rfactor Rfree: 0.23 / Rfactor Rwork: 0.185
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.3

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