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- PDB-8g25: Crystal Structure of Cathepsin-G and Neutrophil Elastase Inhibite... -

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Basic information

Entry
Database: PDB / ID: 8g25
TitleCrystal Structure of Cathepsin-G and Neutrophil Elastase Inhibited by S. aureus EapH2 at pH 7.5
Components
  • Cathepsin-G
  • MAP domain-containing protein
  • Neutrophil elastase
KeywordsHYDROLASE/INHIBITOR / Protease Inhibitor / Immune Evasion / Neutrophil / S. aureus / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


cathepsin G / biofilm matrix disassembly / neutrophil-mediated killing of gram-positive bacterium / leukocyte elastase / biosynthetic process of antibacterial peptides active against Gram-negative bacteria / neutrophil-mediated killing of fungus / purinergic nucleotide receptor signaling pathway / negative regulation of chemotaxis / acute inflammatory response to antigenic stimulus / negative regulation of T cell activation ...cathepsin G / biofilm matrix disassembly / neutrophil-mediated killing of gram-positive bacterium / leukocyte elastase / biosynthetic process of antibacterial peptides active against Gram-negative bacteria / neutrophil-mediated killing of fungus / purinergic nucleotide receptor signaling pathway / negative regulation of chemotaxis / acute inflammatory response to antigenic stimulus / negative regulation of T cell activation / positive regulation of leukocyte tethering or rolling / response to yeast / leukocyte migration involved in inflammatory response / negative regulation of interleukin-8 production / caspase binding / negative regulation of chemokine production / Suppression of apoptosis / protein metabolic process / neutrophil activation / positive regulation of platelet aggregation / Interleukin-1 processing / Antimicrobial peptides / cytokine binding / pyroptotic inflammatory response / Activation of Matrix Metalloproteinases / neutrophil-mediated killing of gram-negative bacterium / monocyte chemotaxis / Collagen degradation / extracellular matrix disassembly / angiotensin maturation / defense response to fungus / Metabolism of Angiotensinogen to Angiotensins / Pyroptosis / Purinergic signaling in leishmaniasis infection / phagocytosis / response to UV / transcription repressor complex / phagocytic vesicle / Degradation of the extracellular matrix / serine-type peptidase activity / secretory granule / Regulation of Complement cascade / positive regulation of interleukin-8 production / positive regulation of smooth muscle cell proliferation / positive regulation of MAP kinase activity / protein catabolic process / protein processing / platelet activation / cytokine-mediated signaling pathway / negative regulation of inflammatory response / cytoplasmic stress granule / intracellular calcium ion homeostasis / specific granule lumen / transcription corepressor activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of immune response / azurophil granule lumen / heparin binding / peptidase activity / antibacterial humoral response / cellular response to lipopolysaccharide / collagen-containing extracellular matrix / defense response to Gram-negative bacterium / endopeptidase activity / protease binding / response to lipopolysaccharide / receptor ligand activity / lysosome / defense response to Gram-positive bacterium / defense response to bacterium / immune response / protein phosphorylation / intracellular membrane-bounded organelle / serine-type endopeptidase activity / Neutrophil degranulation / cell surface / negative regulation of transcription by RNA polymerase II / proteolysis / extracellular space / extracellular exosome / extracellular region / membrane / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
MAP domain / MAP domain / MAP repeat profile. / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease ...MAP domain / MAP domain / MAP repeat profile. / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
MAP domain-containing protein / Neutrophil elastase / Cathepsin G
Similarity search - Component
Biological speciesStaphylococcus aureus subsp. aureus Mu50 (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsMishra, N.B. / Geisbrecht, B.V.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM140852 United States
CitationJournal: J.Biol.Chem. / Year: 2023
Title: Simultaneous inhibition of two neutrophil serine proteases by the S. aureus innate immune evasion protein EapH2.
Authors: Mishra, N. / Herdendorf, T.J. / Prakash, O. / Geisbrecht, B.V.
History
DepositionFeb 3, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: 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.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 19, 2023Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _pdbx_initial_refinement_model.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin-G
B: Neutrophil elastase
C: MAP domain-containing protein
D: MAP domain-containing protein
E: Neutrophil elastase
F: Cathepsin-G
G: MAP domain-containing protein
H: Neutrophil elastase
I: Cathepsin-G


Theoretical massNumber of molelcules
Total (without water)185,5209
Polymers185,5209
Non-polymers00
Water11,403633
1
A: Cathepsin-G
B: Neutrophil elastase
C: MAP domain-containing protein


Theoretical massNumber of molelcules
Total (without water)61,8403
Polymers61,8403
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3840 Å2
ΔGint-14 kcal/mol
Surface area23860 Å2
MethodPISA
2
D: MAP domain-containing protein
E: Neutrophil elastase
F: Cathepsin-G


Theoretical massNumber of molelcules
Total (without water)61,8403
Polymers61,8403
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3830 Å2
ΔGint-17 kcal/mol
Surface area23980 Å2
MethodPISA
3
G: MAP domain-containing protein
H: Neutrophil elastase
I: Cathepsin-G


Theoretical massNumber of molelcules
Total (without water)61,8403
Polymers61,8403
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3740 Å2
ΔGint-15 kcal/mol
Surface area24520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.147, 68.429, 141.899
Angle α, β, γ (deg.)90.00, 102.76, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Cathepsin-G


Mass: 25397.131 Da / Num. of mol.: 3 / Fragment: C-terminal truncation (UNP residues 21-243) / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: neutrophil / References: UniProt: P08311
#2: Protein Neutrophil elastase / Bone marrow serine protease / Elastase-2 / Human leukocyte elastase / HLE / Medullasin / PMN elastase


Mass: 23318.982 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: neutrophil / References: UniProt: P08246, leukocyte elastase
#3: Protein MAP domain-containing protein


Mass: 13123.912 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus subsp. aureus Mu50 (bacteria)
Gene: SAV0981 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A0A0H3JUK5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 633 / 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: 2.2 Å3/Da / Density % sol: 44.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M HEPES, 0.2 M lithium sulfate, 26% w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 149744 / % possible obs: 98.1 % / Redundancy: 3.3 % / CC1/2: 0.979 / Rpim(I) all: 0.075 / Χ2: 0.111 / Net I/σ(I): 5.1 / Num. measured all: 951665
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Num. unique obsCC1/2Rpim(I) allΧ2% possible all
1.8-1.862.9286200.6170.5880.89897.9
1.86-1.943287460.7890.420.97698.4
1.94-2.032.9279850.850.3251.04795.5
2.03-2.133.3290970.9360.2331.01699.2
2.13-2.273.5290940.9690.2311.10499.3
2.27-2.443.5290590.980.1431.02199.1
2.44-2.693.5288340.9880.1081.07898.7
2.69-3.083.4282260.9940.0691.06896.3
3.08-3.883.7291100.9950.0461.07299.6
3.88-503.5285860.9790.0621.15697.5

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Processing

Software
NameVersionClassification
PHENIXv1.19.2refinement
SCALEPACKdata scaling
DENZOdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 1AU8, 1HNE, & 1YN5

1au8

1hne

1yn5


Resolution: 1.8→46.13 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 0.17 / Phase error: 35.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2827 1833 1.37 %
Rwork0.2482 --
obs0.2486 133623 89.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→46.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12702 0 0 633 13335
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00412930
X-RAY DIFFRACTIONf_angle_d0.72117490
X-RAY DIFFRACTIONf_dihedral_angle_d14.3484851
X-RAY DIFFRACTIONf_chiral_restr0.0531944
X-RAY DIFFRACTIONf_plane_restr0.0062307
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.36361220.34488167X-RAY DIFFRACTION73
1.85-1.90.31431220.32858824X-RAY DIFFRACTION78
1.9-1.960.33031300.30599245X-RAY DIFFRACTION82
1.96-2.030.32111310.29929191X-RAY DIFFRACTION82
2.03-2.110.30891410.275510007X-RAY DIFFRACTION89
2.11-2.210.29111410.261810357X-RAY DIFFRACTION91
2.21-2.330.29971460.26310424X-RAY DIFFRACTION92
2.33-2.470.37011380.265710651X-RAY DIFFRACTION94
2.47-2.660.32431480.264810810X-RAY DIFFRACTION95
2.66-2.930.30891590.255410556X-RAY DIFFRACTION93
2.93-3.360.28191460.238511183X-RAY DIFFRACTION98
3.36-4.230.21031560.211211340X-RAY DIFFRACTION99
4.23-46.130.27311530.229511035X-RAY DIFFRACTION95

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