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- PDB-9si4: Structure of human neutrophil elastase in complex with a 5,8-dihy... -

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Basic information

Entry
Database: PDB / ID: 9si4
TitleStructure of human neutrophil elastase in complex with a 5,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one inhibitor
ComponentsNeutrophil elastase
KeywordsHYDROLASE / Trypsin Family Fold / Protease / Hydrolase-Inhibitor Complex
Function / homology
Function and homology information


leukocyte elastase / biosynthetic process of antibacterial peptides active against Gram-negative bacteria / Expression of NOTCH2NL genes / acute inflammatory response to antigenic stimulus / neutrophil-mediated killing of fungus / negative regulation of chemotaxis / positive regulation of leukocyte tethering or rolling / response to yeast / leukocyte migration involved in inflammatory response / negative regulation of chemokine production ...leukocyte elastase / biosynthetic process of antibacterial peptides active against Gram-negative bacteria / Expression of NOTCH2NL genes / acute inflammatory response to antigenic stimulus / neutrophil-mediated killing of fungus / negative regulation of chemotaxis / positive regulation of leukocyte tethering or rolling / response to yeast / leukocyte migration involved in inflammatory response / negative regulation of chemokine production / negative regulation of interleukin-8 production / Antimicrobial peptides / neutrophil-mediated killing of gram-negative bacterium / Activation of Matrix Metalloproteinases / cytokine binding / pyroptotic inflammatory response / positive regulation of MAP kinase activity / Collagen degradation / extracellular matrix disassembly / Pyroptosis / phagocytosis / response to UV / phagocytic vesicle / Degradation of the extracellular matrix / transcription repressor complex / positive regulation of smooth muscle cell proliferation / secretory granule / Regulation of Complement cascade / positive regulation of interleukin-8 production / protein catabolic process / positive regulation of immune response / negative regulation of inflammatory response / specific granule lumen / intracellular calcium ion homeostasis / azurophil granule lumen / transcription corepressor activity / peptidase activity / heparin binding / : / protease binding / endopeptidase activity / response to lipopolysaccharide / defense response to bacterium / serine-type endopeptidase activity / intracellular membrane-bounded organelle / Neutrophil degranulation / cell surface / negative regulation of transcription by RNA polymerase II / Golgi apparatus / proteolysis / extracellular space / extracellular exosome / extracellular region / cytosol / cytoplasm
Similarity search - Function
: / 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 ...: / 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
: / alpha-L-fucopyranose / Neutrophil elastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.14 Å
AuthorsRizzi, A. / Armani, E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Design, Synthesis, and Biological Evaluation of the Novel Neutrophil Elastase Inhibitor CHF-6333 for the Inhaled Treatment of Bronchiectasis.
Authors: Armani, E. / Rizzi, A. / Miglietta, D. / Bassanetti, I. / Amadei, F. / Brogin, G. / Capaldi, C. / Rancati, F. / Carnini, C. / Xanxo Fernandez, S. / Civelli, M. / Puccini, P. / Bellini, M. / ...Authors: Armani, E. / Rizzi, A. / Miglietta, D. / Bassanetti, I. / Amadei, F. / Brogin, G. / Capaldi, C. / Rancati, F. / Carnini, C. / Xanxo Fernandez, S. / Civelli, M. / Puccini, P. / Bellini, M. / Jennings, A. / Heald, R.A. / Alcaraz, L. / Sutton, J.M. / Finch, H. / Fitzgerald, M. / Fox, C. / Villetti, G.
History
DepositionAug 28, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 10, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Neutrophil elastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0567
Polymers23,3191
Non-polymers1,7376
Water2,540141
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1790 Å2
ΔGint26 kcal/mol
Surface area10120 Å2
Unit cell
Length a, b, c (Å)73.160, 73.160, 70.150
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Neutrophil elastase


Mass: 23318.982 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P08246

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Sugars , 3 types, 5 molecules

#2: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#3: 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.: 3 / 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
#4: Sugar ChemComp-FUC / alpha-L-fucopyranose / alpha-L-fucose / 6-deoxy-alpha-L-galactopyranose / L-fucose / fucose


Type: L-saccharide, alpha linking / Mass: 164.156 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H12O5
IdentifierTypeProgram
LFucpaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
a-L-fucopyranoseCOMMON NAMEGMML 1.0
a-L-FucpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
FucSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 142 molecules

#5: Chemical ChemComp-A1JN2 / methyl (5~{R})-5-[4-cyano-2-[2-(trimethyl-$l^{4}-azanyl)ethyl]phenyl]-7-methyl-3-oxidanylidene-8-[3-(trifluoromethyl)phenyl]-2,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylate


Mass: 541.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H28F3N6O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 141 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.32 Å3/Da / Density % sol: 47.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 18% PEG-3350, 0.2M ammonium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 30, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.14→36.61 Å / Num. obs: 61016 / % possible obs: 78.8 % / Redundancy: 8.8 % / Rmerge(I) obs: 0.035 / Net I/σ(I): 33.7
Reflection shellResolution: 1.14→1.17 Å / Rmerge(I) obs: 0.329 / Num. unique obs: 1087

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Processing

Software
NameVersionClassification
PDB-REDOrefinement
PHASER2.8phasing
xia20.3.8.0data scaling
Coot1.1.xmodel building
autoPROCdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.14→36.61 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.973 / SU B: 0.864 / SU ML: 0.018 / Cross valid method: THROUGHOUT / ESU R: 0.036 / ESU R Free: 0.035 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1549 3094 5.1 %RANDOM
Rwork0.13402 ---
obs0.13507 57914 78.65 %-
Solvent computationIon probe radii: 1 Å / Shrinkage radii: 1 Å / VDW probe radii: 1.3 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.267 Å2
Baniso -1Baniso -2Baniso -3
1-0.25 Å20.12 Å20 Å2
2--0.25 Å2-0 Å2
3----0.8 Å2
Refinement stepCycle: LAST / Resolution: 1.14→36.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1636 0 115 141 1892
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0161808
X-RAY DIFFRACTIONr_bond_other_d0.0010.0161691
X-RAY DIFFRACTIONr_angle_refined_deg1.4031.822475
X-RAY DIFFRACTIONr_angle_other_deg0.5041.5573849
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5385.396240
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.95210258
X-RAY DIFFRACTIONr_chiral_restr0.0760.2289
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022219
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02448
X-RAY DIFFRACTIONr_mcbond_it7.1791.523882
X-RAY DIFFRACTIONr_mcbond_other7.1561.521881
X-RAY DIFFRACTIONr_mcangle_it9.5772.7441103
X-RAY DIFFRACTIONr_mcangle_other9.6152.7491104
X-RAY DIFFRACTIONr_scbond_it19.9792.157926
X-RAY DIFFRACTIONr_scbond_other20.3992.199886
X-RAY DIFFRACTIONr_scangle_other20.9853.8041309
X-RAY DIFFRACTIONr_long_range_B_refined18.90219.031943
X-RAY DIFFRACTIONr_long_range_B_other18.81518.451882
X-RAY DIFFRACTIONr_rigid_bond_restr4.3933499
LS refinement shellResolution: 1.14→1.17 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.24 48 -
Rwork0.256 1087 -
obs--19.92 %

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