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- PDB-5a8z: Crystal Structure of human neutrophil elastase in complex with a ... -

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Basic information

Entry
Database: PDB / ID: 5a8z
TitleCrystal Structure of human neutrophil elastase in complex with a dihydropyrimidone 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 / neutrophil-mediated killing of fungus / negative regulation of chemotaxis / acute inflammatory response to antigenic stimulus / positive regulation of leukocyte tethering or rolling / response to yeast / leukocyte migration involved in inflammatory response / negative regulation of interleukin-8 production / negative regulation of chemokine production ...leukocyte elastase / biosynthetic process of antibacterial peptides active against Gram-negative bacteria / neutrophil-mediated killing of fungus / negative regulation of chemotaxis / acute inflammatory response to antigenic stimulus / positive regulation of leukocyte tethering or rolling / response to yeast / leukocyte migration involved in inflammatory response / negative regulation of interleukin-8 production / negative regulation of chemokine production / Antimicrobial peptides / pyroptotic inflammatory response / Activation of Matrix Metalloproteinases / cytokine binding / neutrophil-mediated killing of gram-negative bacterium / Collagen degradation / extracellular matrix disassembly / Pyroptosis / response to UV / phagocytosis / phagocytic vesicle / Degradation of the extracellular matrix / transcription repressor complex / positive regulation of MAP kinase activity / secretory granule / Regulation of Complement cascade / positive regulation of interleukin-8 production / positive regulation of smooth muscle cell proliferation / protein catabolic process / positive regulation of immune response / negative regulation of inflammatory response / specific granule lumen / intracellular calcium ion homeostasis / transcription corepressor activity / azurophil granule lumen / peptidase activity / heparin binding / protease binding / : / endopeptidase activity / response to lipopolysaccharide / defense response to bacterium / serine-type endopeptidase activity / Neutrophil degranulation / negative regulation of transcription by RNA polymerase II / cell surface / 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 / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-IUL / Neutrophil elastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2 Å
Authorsvon Nussbaum, F. / Li, V.M. / Meibom, D. / Anlauf, S. / Bechem, M. / Delbeck, M. / Gerisch, M. / Harrenga, A. / Karthaus, D. / Lang, D. ...von Nussbaum, F. / Li, V.M. / Meibom, D. / Anlauf, S. / Bechem, M. / Delbeck, M. / Gerisch, M. / Harrenga, A. / Karthaus, D. / Lang, D. / Lustig, K. / Mittendorf, J. / Schaefer, M. / Schaefer, S. / Schamberger, J.
CitationJournal: ChemMedChem / Year: 2016
Title: Potent and Selective Human Neutrophil Elastase Inhibitors with Novel Equatorial Ring Topology: in vivo Efficacy of the Polar Pyrimidopyridazine BAY-8040 in a Pulmonary Arterial Hypertension Rat Model.
Authors: von Nussbaum, F. / Li, V.M. / Meibom, D. / Anlauf, S. / Bechem, M. / Delbeck, M. / Gerisch, M. / Harrenga, A. / Karthaus, D. / Lang, D. / Lustig, K. / Mittendorf, J. / Schafer, M. / Schafer, S. / Schamberger, J.
History
DepositionJul 17, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 3, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2Dec 12, 2018Group: Advisory / Data collection ...Advisory / Data collection / Database references / Source and taxonomy / Structure summary
Category: audit_author / citation ...audit_author / citation / citation_author / entity / entity_name_com / entity_src_nat / pdbx_entity_src_syn / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_residues / struct_ref
Item: _audit_author.name / _citation.journal_abbrev ..._audit_author.name / _citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name / _entity.details / _entity.pdbx_description / _entity.src_method / _entity_name_com.name / _pdbx_poly_seq_scheme.pdb_seq_num / _pdbx_unobs_or_zero_occ_residues.auth_seq_id / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Other / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_database_status.status_code_sf / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 7-STRANDED BARREL THIS IS REPRESENTED BY A 8-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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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)24,7025
Polymers23,3191
Non-polymers1,3834
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.119, 73.119, 70.162
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

#1: 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 / Details: purchased commercially / Source: (natural) Homo sapiens (human) / References: UniProt: P08246, leukocyte elastase
#2: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
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.: 1
Source method: isolated from a genetically manipulated source
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: Chemical ChemComp-IUL / 4-[(4R)-7-methyl-2,5-bis(oxidanylidene)-1-[3-(trifluoromethyl)phenyl]-3,4,6,8-tetrahydropyrimido[4,5-d]pyridazin-4-yl]benzenecarbonitrile


Mass: 427.379 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16F3N5O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 91 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.32 Å3/Da / Density % sol: 47.02 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→30.69 Å / Num. obs: 16452 / % possible obs: 95.5 % / Observed criterion σ(I): 0 / Redundancy: 8.71 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 6.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2→63.37 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.927 / SU B: 4.064 / SU ML: 0.117 / Cross valid method: THROUGHOUT / ESU R: 0.205 / ESU R Free: 0.175 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23644 720 5 %RANDOM
Rwork0.18993 ---
obs0.19224 13580 98.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.703 Å2
Baniso -1Baniso -2Baniso -3
1-0.41 Å20.21 Å20 Å2
2--0.41 Å20 Å2
3----0.62 Å2
Refinement stepCycle: LAST / Resolution: 2→63.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1606 0 93 91 1790
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0211739
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5022.0022377
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7595213
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.60422.53571
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.74815248
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7591517
X-RAY DIFFRACTIONr_chiral_restr0.0960.2280
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021312
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2030.2749
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3080.21169
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.130.2103
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1620.235
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1130.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8611.51092
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.39821694
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.0363724
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.1674.5683
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.289 44
Rwork0.23 989

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