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- PDB-5ikv: The Structure of Flufenamic Acid Bound to Human Cyclooxygenase-2 -

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Basic information

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


Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 SPMs / 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 / cellular response to non-ionic osmotic stress / positive regulation of platelet-derived growth factor production / lipoxygenase pathway / hair cycle ...Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 SPMs / 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 / cellular response to non-ionic osmotic stress / positive regulation of platelet-derived growth factor production / lipoxygenase pathway / hair cycle / cellular response to homocysteine / positive regulation of fibroblast growth factor production / prostaglandin-endoperoxide synthase / prostaglandin-endoperoxide synthase activity / cyclooxygenase pathway / positive regulation of transforming growth factor beta production / cellular response to lead ion / negative regulation of synaptic transmission, dopaminergic / negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress / positive regulation of prostaglandin biosynthetic process / regulation of neuroinflammatory response / positive regulation of synaptic plasticity / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / response to fatty acid / response to fructose / positive regulation of smooth muscle contraction / Nicotinamide salvage / oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen / positive regulation of fever generation / response to vitamin D / prostaglandin secretion / cellular response to fluid shear stress / response to selenium ion / response to nematode / nuclear outer membrane / response to angiotensin / nuclear inner membrane / long-chain fatty acid biosynthetic process / response to manganese ion / prostaglandin biosynthetic process / negative regulation of smooth muscle contraction / positive regulation of cell migration involved in sprouting angiogenesis / cellular response to ATP / maintenance of blood-brain barrier / Interleukin-10 signaling / bone mineralization / negative regulation of calcium ion transport / negative regulation of cell cycle / decidualization / response to tumor necrosis factor / positive regulation of vascular endothelial growth factor production / brown fat cell differentiation / response to glucocorticoid / positive regulation of vasoconstriction / positive regulation of brown fat cell differentiation / embryo implantation / positive regulation of synaptic transmission, glutamatergic / learning / positive regulation of smooth muscle cell proliferation / peroxidase activity / caveola / regulation of blood pressure / memory / positive regulation of protein import into nucleus / cellular response to mechanical stimulus / positive regulation of nitric oxide biosynthetic process / response to estradiol / cellular response to heat / cellular response to lipopolysaccharide / regulation of inflammatory response / Interleukin-4 and Interleukin-13 signaling / angiogenesis / cellular response to hypoxia / response to oxidative stress / neuron projection / positive regulation of apoptotic process / endoplasmic reticulum lumen / response to xenobiotic stimulus / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / enzyme binding / endoplasmic reticulum / protein homodimerization activity / protein-containing complex / 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 / 2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID / AMMONIUM ION / Prostaglandin G/H synthase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.508 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: Advisory / Author supporting evidence ...Advisory / Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support ...citation / pdbx_audit_support / pdbx_struct_oper_list / pdbx_unobs_or_zero_occ_atoms
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: Atomic model / Data collection ...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_struct_special_symmetry / 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.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.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_struct_special_symmetry.label_asym_id / _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 2.1Oct 23, 2024Group: Advisory / Data collection ...Advisory / 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_unobs_or_zero_occ_atoms / 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)130,72220
Polymers126,8512
Non-polymers3,87218
Water7,548419
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12560 Å2
ΔGint6 kcal/mol
Surface area41590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)126.918, 149.334, 184.766
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-880-

HOH

21A-882-

HOH

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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
#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.: 2
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
#7: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0

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Non-polymers , 4 types, 432 molecules

#3: Chemical ChemComp-FLF / 2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID / FLUFENAMIC ACID


Mass: 281.230 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C14H10F3NO2 / Comment: antiinflammatory, inhibitor*YM
#4: 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-NH4 / AMMONIUM ION


Mass: 18.038 Da / Num. of mol.: 9
Source method: isolated from a genetically manipulated source
Formula: H4N
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 419 / 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: 3.36 Å3/Da / Density % sol: 63.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 32% PEG 400, 100mM 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: 2.5→30 Å / Num. obs: 60238 / % possible obs: 100 % / Redundancy: 6.2 % / Net I/σ(I): 22.4

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.508→30.009 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2238 2952 5.04 %
Rwork0.1854 --
obs0.1874 58538 97.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.508→30.009 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8940 0 261 419 9620
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0119494
X-RAY DIFFRACTIONf_angle_d0.89812899
X-RAY DIFFRACTIONf_dihedral_angle_d15.2393489
X-RAY DIFFRACTIONf_chiral_restr0.0361351
X-RAY DIFFRACTIONf_plane_restr0.0051658
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5082-2.54940.28881020.24691952X-RAY DIFFRACTION72
2.5494-2.59330.27491100.2432196X-RAY DIFFRACTION81
2.5933-2.64040.27591240.24212493X-RAY DIFFRACTION92
2.6404-2.69120.27441340.23482589X-RAY DIFFRACTION97
2.6912-2.74610.27461640.23222653X-RAY DIFFRACTION99
2.7461-2.80570.25861550.22442708X-RAY DIFFRACTION100
2.8057-2.8710.2521500.2222673X-RAY DIFFRACTION100
2.871-2.94270.23321400.2182689X-RAY DIFFRACTION100
2.9427-3.02220.23641310.20782710X-RAY DIFFRACTION100
3.0222-3.1110.25791470.22432699X-RAY DIFFRACTION100
3.111-3.21130.27571590.2132706X-RAY DIFFRACTION100
3.2113-3.3260.28961380.20912697X-RAY DIFFRACTION100
3.326-3.45890.25771620.19282710X-RAY DIFFRACTION100
3.4589-3.61610.22071430.17612720X-RAY DIFFRACTION100
3.6161-3.80640.19061370.16172721X-RAY DIFFRACTION100
3.8064-4.04440.18321290.1552742X-RAY DIFFRACTION100
4.0444-4.35580.20121350.15352752X-RAY DIFFRACTION100
4.3558-4.79250.17271470.14172741X-RAY DIFFRACTION100
4.7925-5.48230.16121390.14662772X-RAY DIFFRACTION100
5.4823-6.89330.23671340.19312786X-RAY DIFFRACTION100
6.8933-30.0110.21261720.18412877X-RAY DIFFRACTION100
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)
12.3463-0.1144-1.16141.41970.85221.82810.12030.70220.2106-0.6694-0.13980.169-0.2742-0.3228-0.01010.7315-0.0524-0.08330.72820.21530.4885155.0628209.9471181.2379
23.0909-1.1523-1.4550.94521.09312.4115-0.02180.3988-0.0818-0.4859-0.0002-0.2122-0.10340.19690.01340.5271-0.04650.15250.60620.03820.4542176.0433190.7128187.2144
31.3570.69170.50233.69341.62353.5806-0.20310.42220.0613-0.616-0.08820.49640.0154-0.37350.29020.4235-0.0304-0.06230.59420.04790.4389144.5148193.9383189.4548
41.2210.02660.17431.8687-0.06371.3689-0.08260.2859-0.2938-0.2160.11640.06380.2851-0.0853-0.03870.4072-0.0070.07870.407-0.02340.3825160.3658178.3703200.2305
51.02230.6250.01252.09790.00810.7888-0.02920.12460.12380.16650.0853-0.39230.0270.2551-0.04780.33520.03070.00990.43950.03980.4143176.1719208.3086217.5594
61.5910.16220.31111.64950.24070.8218-0.0497-0.10770.35190.1448-0.02140.3896-0.0047-0.07980.07330.32830.05640.05820.31740.04380.4877150.183215.642217.3023
73.5248-0.93050.79911.2944-0.03610.9273-0.0878-0.67210.750.4961-0.03680.4801-0.2396-0.30780.10820.5590.07150.110.5773-0.15350.9617143.875229.9421227.6988
81.64270.22580.61861.59410.25621.89840.0067-0.16070.38460.3233-0.01180.0526-0.05880.09640.00610.35990.00860.06030.33680.01920.4474163.7284218.9949223.6028
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 34:80)
2X-RAY DIFFRACTION2(chain A and resid 81:128)
3X-RAY DIFFRACTION3(chain A and resid 129:183)
4X-RAY DIFFRACTION4(chain A and resid 184:583)
5X-RAY DIFFRACTION5(chain B and resid 34:155)
6X-RAY DIFFRACTION6(chain B and resid 156:386)
7X-RAY DIFFRACTION7(chain B and resid 387:428)
8X-RAY DIFFRACTION8(chain B and resid 429:583)

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