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- PDB-5ikt: The Structure of Tolfenamic Acid Bound to Human Cyclooxygenase-2 -

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Basic information

Entry
Database: PDB / ID: 5ikt
TitleThe Structure of Tolfenamic Acid Bound to Human Cyclooxygenase-2
ComponentsProstaglandin G/H synthase 2
KeywordsOXIDOREDUCTASE / COX Tolfenamic
Function / homology
Function and homology information


Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 SPMs / positive regulation of platelet-derived growth factor production / Biosynthesis of DHA-derived SPMs / Biosynthesis of electrophilic ω-3 PUFA oxo-derivatives / oxidoreductase activity, acting on single donors with incorporation of molecular oxygen / Synthesis of 15-eicosatetraenoic acid derivatives / positive regulation of fibroblast growth factor production / cellular response to non-ionic osmotic stress / lipoxygenase pathway ...Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 SPMs / positive regulation of platelet-derived growth factor production / Biosynthesis of DHA-derived SPMs / Biosynthesis of electrophilic ω-3 PUFA oxo-derivatives / oxidoreductase activity, acting on single donors with incorporation of molecular oxygen / Synthesis of 15-eicosatetraenoic acid derivatives / positive regulation of fibroblast growth factor production / cellular response to non-ionic osmotic stress / lipoxygenase pathway / positive regulation of transforming growth factor beta production / prostaglandin-endoperoxide synthase / prostaglandin-endoperoxide synthase activity / cyclooxygenase pathway / negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress / positive regulation of prostaglandin biosynthetic process / oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen / regulation of neuroinflammatory response / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / : / response to selenium ion / positive regulation of fever generation / prostaglandin secretion / cellular response to fluid shear stress / response to nematode / nuclear inner membrane / prostaglandin biosynthetic process / positive regulation of cell migration involved in sprouting angiogenesis / long-chain fatty acid biosynthetic process / Interleukin-10 signaling / nuclear outer membrane / positive regulation of vascular endothelial growth factor production / decidualization / brown fat cell differentiation / positive regulation of brown fat cell differentiation / embryo implantation / peroxidase activity / regulation of blood pressure / positive regulation of nitric oxide biosynthetic process / regulation of cell population proliferation / regulation of inflammatory response / Interleukin-4 and Interleukin-13 signaling / cellular response to hypoxia / response to oxidative stress / neuron projection / endoplasmic reticulum lumen / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / enzyme binding / endoplasmic reticulum / protein homodimerization activity / metal ion binding / cytosol / cytoplasm
Similarity search - Function
: / Myeloperoxidase, subunit C / Haem peroxidase domain superfamily, animal type / Haem peroxidase, animal-type / Haem peroxidase domain superfamily, animal type / Animal haem peroxidase / Animal heme peroxidase superfamily profile. / Laminin / Laminin / EGF-like domain ...: / Myeloperoxidase, subunit C / Haem peroxidase domain superfamily, animal type / Haem peroxidase, animal-type / Haem peroxidase domain superfamily, animal type / Animal haem peroxidase / Animal heme peroxidase superfamily profile. / Laminin / Laminin / EGF-like domain / Haem peroxidase superfamily / EGF-like domain profile. / EGF-like domain / Ribbon / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING CO / PHOSPHATE ION / 2-[(3-chloro-2-methylphenyl)amino]benzoic acid / Prostaglandin G/H synthase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.451 Å
AuthorsOrlando, B.J. / Malkowski, M.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM115386 United States
CitationJournal: J.Biol.Chem. / Year: 2016
Title: Substrate-selective Inhibition of Cyclooxygeanse-2 by Fenamic Acid Derivatives Is Dependent on Peroxide Tone.
Authors: Orlando, B.J. / Malkowski, M.G.
History
DepositionMar 3, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 25, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 8, 2016Group: Data collection / Database references
Revision 1.2Jul 27, 2016Group: Database references
Revision 1.3Sep 27, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / 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 / pdbx_struct_conn_angle / pdbx_validate_close_contact / 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 / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Nov 13, 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 / pdbx_validate_chiral
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Prostaglandin G/H synthase 2
B: Prostaglandin G/H synthase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,42617
Polymers126,8512
Non-polymers4,57515
Water7,584421
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11810 Å2
ΔGint-54 kcal/mol
Surface area41840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)126.669, 149.759, 185.726
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Prostaglandin G/H synthase 2 / Cyclooxygenase-2 / COX-2 / PHS II / Prostaglandin H2 synthase 2 / PGHS-2 / Prostaglandin- ...Cyclooxygenase-2 / COX-2 / PHS II / Prostaglandin H2 synthase 2 / PGHS-2 / Prostaglandin-endoperoxide synthase 2


Mass: 63425.336 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTGS2, COX2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35354, prostaglandin-endoperoxide synthase

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Sugars , 3 types, 5 molecules

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


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1a_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#3: 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.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#7: 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

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Non-polymers , 4 types, 431 molecules

#4: Chemical ChemComp-TLF / 2-[(3-chloro-2-methylphenyl)amino]benzoic acid / Tolfenamic acid


Mass: 261.704 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C14H12ClNO2 / Comment: antiinflammatory, inhibitor*YM
#5: Chemical ChemComp-COH / PROTOPORPHYRIN IX CONTAINING CO


Mass: 619.575 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C34H32CoN4O4
#6: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: PO4
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 421 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.37 Å3/Da / Density % sol: 63.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 32% PEG 400, 100 mM HEPES, 300mM ammonium phosphate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.45→30 Å / Num. obs: 64987 / % possible obs: 99.8 % / Redundancy: 4.9 % / Net I/σ(I): 19.2

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.451→29.972 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.99 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2196 3113 4.94 %
Rwork0.1795 --
obs0.1815 63042 97.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.451→29.972 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8925 0 300 421 9646
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0049525
X-RAY DIFFRACTIONf_angle_d0.82812953
X-RAY DIFFRACTIONf_dihedral_angle_d15.4153487
X-RAY DIFFRACTIONf_chiral_restr0.0311361
X-RAY DIFFRACTIONf_plane_restr0.0041662
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4505-2.48880.27731020.24022107X-RAY DIFFRACTION75
2.4888-2.52960.29231150.24672239X-RAY DIFFRACTION81
2.5296-2.57320.32391270.23642428X-RAY DIFFRACTION88
2.5732-2.61990.27761420.24632679X-RAY DIFFRACTION96
2.6199-2.67030.26411480.23312749X-RAY DIFFRACTION99
2.6703-2.72480.2991500.23142754X-RAY DIFFRACTION99
2.7248-2.7840.29581520.22692764X-RAY DIFFRACTION100
2.784-2.84870.28831560.21982767X-RAY DIFFRACTION100
2.8487-2.91990.24841260.22222812X-RAY DIFFRACTION100
2.9199-2.99880.22131430.20822811X-RAY DIFFRACTION100
2.9988-3.08690.27311370.21152765X-RAY DIFFRACTION100
3.0869-3.18640.28731640.21052760X-RAY DIFFRACTION100
3.1864-3.30020.23891500.20872801X-RAY DIFFRACTION100
3.3002-3.43210.22781380.192789X-RAY DIFFRACTION100
3.4321-3.58810.22951410.17242817X-RAY DIFFRACTION100
3.5881-3.77690.21081370.16352805X-RAY DIFFRACTION100
3.7769-4.01310.16931490.15452794X-RAY DIFFRACTION100
4.0131-4.32210.18881460.14682818X-RAY DIFFRACTION100
4.3221-4.75550.19641340.13522837X-RAY DIFFRACTION100
4.7555-5.440.14791530.13272839X-RAY DIFFRACTION100
5.44-6.84040.18161640.16792833X-RAY DIFFRACTION99
6.8404-29.97470.19441390.16182961X-RAY DIFFRACTION99

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