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- PDB-8g26: Crystal Structure of Cathepsin-G and Neutrophil Elastase Inhibite... -

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Basic information

Entry
Database: PDB / ID: 8g26
TitleCrystal Structure of Cathepsin-G and Neutrophil Elastase Inhibited by S. aureus EapH2 at pH 8.5
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 / Expression of NOTCH2NL genes / negative regulation of chemotaxis / purinergic nucleotide receptor signaling pathway / acute inflammatory response to antigenic stimulus ...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 / Expression of NOTCH2NL genes / negative regulation of chemotaxis / purinergic nucleotide receptor signaling pathway / acute inflammatory response to antigenic stimulus / caspase binding / positive regulation of leukocyte tethering or rolling / response to yeast / negative regulation of T cell activation / leukocyte migration involved in inflammatory response / negative regulation of interleukin-8 production / negative regulation of chemokine production / neutrophil activation / Suppression of apoptosis / Interleukin-1 processing / positive regulation of platelet aggregation / Antimicrobial peptides / pyroptotic inflammatory response / Activation of Matrix Metalloproteinases / cytokine binding / neutrophil-mediated killing of gram-negative bacterium / monocyte chemotaxis / Collagen degradation / extracellular matrix disassembly / Pyroptosis / defense response to fungus / phagocytosis / Purinergic signaling in leishmaniasis infection / response to UV / Metabolism of Angiotensinogen to Angiotensins / angiotensin maturation / phagocytic vesicle / Degradation of the extracellular matrix / transcription repressor complex / serine-type peptidase activity / positive regulation of MAP kinase activity / protein maturation / secretory granule / Regulation of Complement cascade / positive regulation of interleukin-8 production / positive regulation of smooth muscle cell proliferation / protein catabolic process / cytokine-mediated signaling pathway / protein processing / positive regulation of immune response / platelet activation / negative regulation of inflammatory response / specific granule lumen / intracellular calcium ion homeostasis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cytoplasmic stress granule / transcription corepressor activity / azurophil granule lumen / antibacterial humoral response / peptidase activity / heparin binding / cellular response to lipopolysaccharide / protease binding / : / defense response to Gram-negative bacterium / endopeptidase activity / response to lipopolysaccharide / lysosome / defense response to Gram-positive bacterium / defense response to bacterium / immune response / protein phosphorylation / receptor ligand activity / serine-type endopeptidase activity / intracellular membrane-bounded organelle / Neutrophil degranulation / negative regulation of transcription by RNA polymerase II / cell surface / Golgi apparatus / proteolysis / extracellular space / extracellular exosome / extracellular region / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
MAP domain / MAP domain / MAP repeat profile. / : / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. ...MAP domain / MAP domain / MAP repeat profile. / : / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / 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: 1.85 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
Revision 1.4Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,4865
Polymers61,8403
Non-polymers6462
Water3,945219
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization, Functional assay for enzyme inhibition
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4410 Å2
ΔGint-7 kcal/mol
Surface area24120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.459, 68.923, 82.524
Angle α, β, γ (deg.)90.00, 102.38, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein Cathepsin-G


Mass: 25397.131 Da / Num. of mol.: 1 / 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.: 1 / 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.: 1
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

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Sugars , 2 types, 2 molecules

#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 1 types, 219 molecules

#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 219 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
Has protein modificationY

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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: 2.22 Å3/Da / Density % sol: 44.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 0.1 M Tris, 0.2 M magnesium chloride, 25% 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: 1.85→50 Å / Num. obs: 46050 / % possible obs: 98.8 % / Redundancy: 3.3 % / CC1/2: 0.984 / Rpim(I) all: 0.063 / Χ2: 0.092 / Net I/σ(I): 11.7 / Num. measured all: 293741
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Num. unique obsCC1/2Rpim(I) allΧ2% possible all
1.85-1.92389760.560.6570.89899.4
1.92-1.993.289100.7230.4421.07399.7
1.99-2.083.389580.8260.3260.97499.6
2.08-2.193.389270.9050.211.04299.4
2.19-2.333.389590.9350.1511.0699.1
2.33-2.513.287220.9580.1111.03697.2
2.51-2.763.386470.9750.0811.00496.2
2.76-3.163.689960.9820.0641.07199.9
3.16-3.993.589250.990.0471.16299.6
3.99-503.488200.9920.0381.09597.7

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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: 1.85→39.56 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 25.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2376 1918 4.38 %
Rwork0.2028 --
obs0.2043 43792 95.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→39.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4235 0 42 219 4496
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074353
X-RAY DIFFRACTIONf_angle_d0.8885889
X-RAY DIFFRACTIONf_dihedral_angle_d15.2861636
X-RAY DIFFRACTIONf_chiral_restr0.057663
X-RAY DIFFRACTIONf_plane_restr0.009773
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.90.35931130.31532550X-RAY DIFFRACTION81
1.9-1.950.33081330.29142774X-RAY DIFFRACTION90
1.95-2.010.31241350.26282880X-RAY DIFFRACTION92
2.01-2.070.27031390.24932926X-RAY DIFFRACTION93
2.07-2.150.26041300.23893003X-RAY DIFFRACTION95
2.15-2.230.29261490.23553008X-RAY DIFFRACTION96
2.23-2.340.26731250.21423043X-RAY DIFFRACTION97
2.34-2.460.26771500.20793037X-RAY DIFFRACTION97
2.46-2.610.24991250.22042932X-RAY DIFFRACTION94
2.61-2.820.28771410.21483108X-RAY DIFFRACTION99
2.82-3.10.26211470.20543174X-RAY DIFFRACTION100
3.1-3.550.20851370.1943145X-RAY DIFFRACTION100
3.55-4.470.19241470.16423141X-RAY DIFFRACTION99
4.47-39.560.20741470.18733153X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
17.2188-0.95672.79877.6238-3.30223.49740.2498-0.37190.20670.71050.14461.1422-0.4418-0.8136-0.54150.3105-0.01420.11850.1538-0.01810.3909-13.792929.117145.3668
21.9241-0.6855-0.42115.761-0.78481.53510.1323-0.08990.17610.3758-0.2134-0.1639-0.20660.2640.07650.2211-0.02430.00210.1188-0.00070.2045-1.266227.834345.3091
32.54181.4681-0.62444.70940.21213.5723-0.48930.4681-0.0329-0.55470.6241-0.2832-0.05330.1508-0.08280.7777-0.1163-0.01221.1137-0.24970.4679-6.43913.833-5.5541
40.3860.6074-0.58221.2739-1.15181.0651-0.04730.8364-0.2691-1.11930.5584-0.5364-0.26821.2422-0.39960.7921-0.24240.09651.6061-0.30320.5728-0.6489.7245-5.3858
51.02310.2772-0.22681.8096-0.00311.5198-0.15620.66190.027-0.81830.28640.0877-0.59240.3163-0.07940.9723-0.198-0.13931.08650.04910.4821-11.575214.2611-8.931
69.2006-0.77293.73879.92081.96648.1347-0.0859-0.7049-0.33680.66470.8975-1.020.9230.4212-0.70150.5690.0592-0.04510.9948-0.28480.5456-7.4307-2.38984.3797
75.09010.3605-0.19253.85820.35782.416-0.3220.6421-0.0911-0.29680.33730.57980.11010.04060.10330.4499-0.1068-0.02830.9538-0.15490.3887-24.62126.6923-0.8623
81.4501-1.97180.28063.010.07233.8926-0.61020.6753-0.1159-0.48060.34260.6513-0.4956-0.03680.23840.6032-0.1785-0.07350.8615-0.1310.468-19.85335.71420.9449
91.13630.3542-2.27643.113-2.09735.2290.10310.75820.5665-0.5927-0.117-0.3046-1.27140.80130.08581.2784-0.3287-0.24781.23170.34980.6052-16.760118.8788-10.3534
106.32181.0589-0.56557.14671.64186.2520.11150.7413-0.2453-0.4348-0.2275-0.39940.37620.21650.14460.35250.0945-0.0090.28640.02550.2221-0.781516.305226.4085
116.7357-2.62930.37921.3989-0.52183.22030.2857-0.62990.7628-0.10.2161-0.8783-0.4291.7574-0.67420.6229-0.11820.151.3432-0.39880.57130.75937.818112.3194
125.9215-0.3618-1.66934.47770.60352.4415-0.18020.7531-0.1511-0.0504-0.1569-0.26510.24830.60860.22940.2330.0486-0.01580.2761-0.01440.2481-9.990711.878124.324
133.17921.2663-4.76124.3314-2.53047.46060.06071.06080.4635-0.49550.04171.11010.1142-0.3001-0.06940.30060.0993-0.15750.43120.10710.2151-15.550418.493123.1249
144.22134.0357-3.00825.0654-3.11144.26960.18540.7625-0.0613-0.4304-0.5188-0.88480.10620.68790.31410.55270.2694-0.05711.0630.25410.3776-6.24122.532712.7743
153.5852.69420.75874.16022.8782.6025-0.19761.12690.1267-0.37520.10.0558-0.2542-0.03520.12550.38650.0517-0.0580.55950.03020.2204-9.79317.372917.044
163.1617-1.98441.73464.6025-4.02376.33440.13580.11930.58470.2436-0.2405-0.9665-0.31950.68410.16890.288-0.0430.01130.25510.03410.532314.820230.648241.9238
173.63210.0559-0.24462.85870.2991.99230.11080.0206-0.08370.1232-0.1364-0.41440.2060.27490.03280.21030.0283-0.01140.13130.05650.27865.759714.941741.4196
185.00891.1182-1.09183.44771.16943.1355-0.1985-0.5464-0.20030.4039-0.0548-1.03540.12030.82040.24870.3848-0.0002-0.15680.35570.15190.545313.742315.737550.9576
193.3492-2.85350.58396.40471.29370.9042-0.0349-0.6644-0.02360.95810.06260.11620.00730.021-0.01360.4529-0.1008-0.05360.22860.04170.32630.373732.858553.284
208.4692-3.0584.83117.0076-3.31433.18960.08721.13620.4059-1.2529-0.2887-0.93530.12660.29120.23030.38810.00310.12150.37630.08920.41739.741928.540129.9125
215.032-3.6166-1.80943.14411.89292.22110.0017-0.21530.25310.108-0.0266-0.1813-0.1608-0.010.03720.3267-0.05040.01420.12080.05540.327-2.852537.023944.3596
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 169 through 178 )
2X-RAY DIFFRACTION2chain 'A' and (resid 179 through 238 )
3X-RAY DIFFRACTION3chain 'B' and (resid 29 through 60 )
4X-RAY DIFFRACTION4chain 'B' and (resid 61 through 95 )
5X-RAY DIFFRACTION5chain 'B' and (resid 96 through 154 )
6X-RAY DIFFRACTION6chain 'B' and (resid 155 through 168 )
7X-RAY DIFFRACTION7chain 'B' and (resid 169 through 183 )
8X-RAY DIFFRACTION8chain 'B' and (resid 184 through 228 )
9X-RAY DIFFRACTION9chain 'B' and (resid 229 through 246 )
10X-RAY DIFFRACTION10chain 'C' and (resid 42 through 68 )
11X-RAY DIFFRACTION11chain 'C' and (resid 69 through 74 )
12X-RAY DIFFRACTION12chain 'C' and (resid 75 through 90 )
13X-RAY DIFFRACTION13chain 'C' and (resid 91 through 109 )
14X-RAY DIFFRACTION14chain 'C' and (resid 110 through 118 )
15X-RAY DIFFRACTION15chain 'C' and (resid 119 through 144 )
16X-RAY DIFFRACTION16chain 'A' and (resid 16 through 29 )
17X-RAY DIFFRACTION17chain 'A' and (resid 30 through 104 )
18X-RAY DIFFRACTION18chain 'A' and (resid 105 through 124 )
19X-RAY DIFFRACTION19chain 'A' and (resid 125 through 141 )
20X-RAY DIFFRACTION20chain 'A' and (resid 142 through 154 )
21X-RAY DIFFRACTION21chain 'A' and (resid 155 through 168 )

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