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- PDB-5ikr: The Structure of Mefenamic Acid Bound to Human Cyclooxygenase-2 -

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Basic information

Entry
Database: PDB / ID: 5ikr
TitleThe Structure of Mefenamic Acid Bound to Human Cyclooxygenase-2
ComponentsProstaglandin G/H synthase 2Cyclooxygenase
KeywordsOXIDOREDUCTASE / COX Mefenamic
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 / Synthesis of 15-eicosatetraenoic acid derivatives / cellular response to non-ionic osmotic stress / positive regulation of platelet-derived growth factor production / hair cycle / positive regulation of fibroblast growth factor production / prostaglandin-endoperoxide synthase ...Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 SPMs / Biosynthesis of DHA-derived SPMs / Biosynthesis of electrophilic ω-3 PUFA oxo-derivatives / Synthesis of 15-eicosatetraenoic acid derivatives / cellular response to non-ionic osmotic stress / positive regulation of platelet-derived growth factor production / hair cycle / positive regulation of fibroblast growth factor production / prostaglandin-endoperoxide synthase / prostaglandin-endoperoxide synthase activity / negative regulation of synaptic transmission, dopaminergic / cellular response to lead ion / response to nematode / positive regulation of transforming growth factor beta production / 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) / oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen / response to fructose / positive regulation of smooth muscle contraction / Nicotinamide salvaging / response to fatty acid / cyclooxygenase pathway / positive regulation of fever generation / response to vitamin D / prostaglandin secretion / cellular response to fluid shear stress / nuclear outer membrane / response to angiotensin / response to manganese ion / prostaglandin biosynthetic process / nuclear inner membrane / cellular response to ATP / negative regulation of smooth muscle contraction / maintenance of blood-brain barrier / positive regulation of cell migration involved in sprouting angiogenesis / bone mineralization / Interleukin-10 signaling / negative regulation of calcium ion transport / decidualization / negative regulation of cell cycle / positive regulation of vascular endothelial growth factor production / response to tumor necrosis factor / brown fat cell differentiation / positive regulation of vasoconstriction / response to glucocorticoid / embryo implantation / positive regulation of brown fat cell differentiation / peroxidase activity / positive regulation of synaptic transmission, glutamatergic / learning / caveola / positive regulation of smooth muscle cell proliferation / memory / regulation of blood pressure / 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 / positive regulation of peptidyl-serine phosphorylation / regulation of inflammatory response / cellular response to hypoxia / angiogenesis / Interleukin-4 and Interleukin-13 signaling / response to oxidative stress / response to lipopolysaccharide / neuron projection / response to xenobiotic stimulus / positive regulation of apoptotic process / endoplasmic reticulum lumen / negative regulation of cell population proliferation / heme binding / endoplasmic reticulum membrane / enzyme binding / endoplasmic reticulum / protein homodimerization activity / protein-containing complex / metal ion binding / 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 / Haem peroxidase superfamily ...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-[(2,3-DIMETHYLPHENYL)AMINO]BENZOIC ACID / AMMONIUM ION / Prostaglandin G/H synthase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.342 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: 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_struct_special_symmetry / 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.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 / _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

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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)131,44819
Polymers126,8512
Non-polymers4,59717
Water8,845491
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11360 Å2
ΔGint-18 kcal/mol
Surface area42250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)127.672, 149.694, 188.391
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-830-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Prostaglandin G/H synthase 2 / Cyclooxygenase / 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, 8 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-Acetylglucosamine


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
#6: Sugar
ChemComp-BOG / octyl beta-D-glucopyranoside / Octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 4
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, 500 molecules

#3: Chemical ChemComp-ID8 / 2-[(2,3-DIMETHYLPHENYL)AMINO]BENZOIC ACID / MEFENAMIC ACID / Mefenamic acid


Mass: 241.285 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C15H15NO2 / Comment: antiinflammatory*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
#7: Chemical
ChemComp-NH4 / AMMONIUM ION / Ammonium


Mass: 18.038 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Formula: H4N
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 491 / Source method: isolated from a natural source / Formula: H2O

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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: 3.43 Å3/Da / Density % sol: 64.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 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: 2.35→30 Å / Num. obs: 75533 / % possible obs: 99.3 % / Redundancy: 5.6 % / Net I/σ(I): 30.1

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementResolution: 2.342→19.995 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 21.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2111 3580 4.95 %
Rwork0.1847 --
obs0.186 72316 95.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.342→19.995 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8940 0 313 491 9744
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0129552
X-RAY DIFFRACTIONf_angle_d0.8412966
X-RAY DIFFRACTIONf_dihedral_angle_d13.9563508
X-RAY DIFFRACTIONf_chiral_restr0.0321366
X-RAY DIFFRACTIONf_plane_restr0.0041658
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3423-2.37310.2164790.24131790X-RAY DIFFRACTION65
2.3731-2.40550.2925970.23852106X-RAY DIFFRACTION76
2.4055-2.43990.27731140.22432156X-RAY DIFFRACTION79
2.4399-2.47620.26491120.23182321X-RAY DIFFRACTION84
2.4762-2.51480.24111160.2242452X-RAY DIFFRACTION89
2.5148-2.5560.26581480.22822607X-RAY DIFFRACTION96
2.556-2.60.27231470.22892689X-RAY DIFFRACTION99
2.6-2.64710.25791340.22332736X-RAY DIFFRACTION99
2.6471-2.69790.23511250.22352709X-RAY DIFFRACTION99
2.6979-2.75290.23881500.2142730X-RAY DIFFRACTION99
2.7529-2.81260.21681350.20362759X-RAY DIFFRACTION99
2.8126-2.87780.26111520.21252724X-RAY DIFFRACTION100
2.8778-2.94960.25251560.21952745X-RAY DIFFRACTION100
2.9496-3.0290.25231520.20442759X-RAY DIFFRACTION100
3.029-3.11790.271550.20252720X-RAY DIFFRACTION100
3.1179-3.21810.22671540.20242744X-RAY DIFFRACTION100
3.2181-3.33260.22671350.19962775X-RAY DIFFRACTION100
3.3326-3.46540.21111630.1822729X-RAY DIFFRACTION100
3.4654-3.62220.17981410.16562769X-RAY DIFFRACTION100
3.6222-3.81190.16881480.15462755X-RAY DIFFRACTION100
3.8119-4.04890.17831330.15462799X-RAY DIFFRACTION100
4.0489-4.35860.16751520.1522778X-RAY DIFFRACTION100
4.3586-4.79170.16211330.14282798X-RAY DIFFRACTION100
4.7917-5.47260.16351380.14672843X-RAY DIFFRACTION100
5.4726-6.84860.20881740.18932804X-RAY DIFFRACTION100
6.8486-19.99540.21761370.18092939X-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)
12.6985-2.04410.08723.87661.19970.6762-0.16970.28120.2856-0.1950.1027-0.9878-0.14980.39920.11660.2232-0.0106-0.01270.47950.07670.55358.110121.376455.3702
20.7324-0.51170.12622.1286-0.64741.0836-0.1664-0.0329-0.13110.0811-0.0152-0.29970.11320.24370.18470.16990.0531-0.00680.32730.06680.271643.99687.70765.3515
31.5750.0366-0.0831.8313-0.10711.1528-0.10410.2129-0.2395-0.16720.02790.40640.1818-0.07790.05720.1625-0.0049-0.03070.1979-0.02580.314223.05675.239959.2664
41.50980.0239-0.58241.7456-0.17151.8557-0.08560.2557-0.2907-0.2872-0.0385-0.08910.12250.16060.11830.19980.0524-0.01480.2463-0.0210.236837.03354.348956.1317
51.3502-0.73191.08092.7373-0.06622.5057-0.1712-0.4529-0.08571.0315-0.04080.0004-0.2253-0.08640.20960.82940.13590.05640.48450.08820.247330.670514.783597.6821
61.32180.33510.16311.03390.61670.7479-0.3164-0.26920.09620.98350.0466-0.1338-0.14040.3836-0.1130.59210.0368-0.37260.46970.08730.27942.278829.974286.0953
71.3019-0.0573-0.40432.1953-0.46911.5696-0.0883-0.10960.42080.5359-0.0113-0.0078-0.64090.03390.05760.502-0.0031-0.21170.2228-0.02290.33232.921145.595773.9585
80.6193-0.06060.32811.4247-0.30040.7154-0.1869-0.40620.35460.8790.0052-0.0864-0.65490.1130.08730.80060.0412-0.20230.4097-0.08470.394435.225141.918487.4171
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 34:83)
2X-RAY DIFFRACTION2(chain A and resid 84:147)
3X-RAY DIFFRACTION3(chain A and resid 148:444)
4X-RAY DIFFRACTION4(chain A and resid 445:583)
5X-RAY DIFFRACTION5(chain B and resid 34:83)
6X-RAY DIFFRACTION6(chain B and resid 84:147)
7X-RAY DIFFRACTION7(chain B and resid 148:421)
8X-RAY DIFFRACTION8(chain B and resid 422:583)

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