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- PDB-5ikq: The Structure of Meclofenamic Acid Bound to Human Cyclooxygenase-2 -

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Basic information

Entry
Database: PDB / ID: 5ikq
TitleThe Structure of Meclofenamic Acid Bound to Human Cyclooxygenase-2
ComponentsProstaglandin G/H synthase 2
KeywordsOXIDOREDUCTASE / COX Meclofenamic
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 / cellular response to homocysteine / positive regulation of fibroblast growth factor production ...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 / cellular response to homocysteine / 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) / positive regulation of smooth muscle contraction / Nicotinamide salvaging / oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen / cyclooxygenase pathway / response to fatty acid / response to fructose / positive regulation of fever generation / prostaglandin secretion / response to vitamin D / cellular response to fluid shear stress / nuclear outer membrane / response to angiotensin / response to manganese ion / prostaglandin biosynthetic process / nuclear inner membrane / negative regulation of smooth muscle contraction / cellular response to ATP / positive regulation of cell migration involved in sprouting angiogenesis / maintenance of blood-brain barrier / 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 / response to glucocorticoid / positive regulation of vasoconstriction / positive regulation of brown fat cell differentiation / embryo implantation / 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 / peroxidase activity / cellular response to mechanical stimulus / positive regulation of nitric oxide biosynthetic process / positive regulation of peptidyl-serine phosphorylation / response to estradiol / cellular response to heat / regulation of inflammatory response / cellular response to hypoxia / angiogenesis / Interleukin-4 and Interleukin-13 signaling / response to oxidative stress / response to lipopolysaccharide / response to xenobiotic stimulus / neuron projection / positive regulation of apoptotic process / negative regulation of cell population proliferation / endoplasmic reticulum lumen / 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
ACRYLIC ACID / PROTOPORPHYRIN IX CONTAINING CO / Chem-JMS / Prostaglandin G/H synthase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 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: 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_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_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _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

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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)131,57316
Polymers126,8512
Non-polymers4,72214
Water7,494416
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11170 Å2
ΔGint-15 kcal/mol
Surface area42490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.509, 134.053, 179.382
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, 7 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpa1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1a_1-5]/1-1-2-2/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#3: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside


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
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4
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, 423 molecules

#4: Chemical ChemComp-JMS / 2-[(2,6-dichloro-3-methyl-phenyl)amino]benzoic acid / meclofenamic acid


Mass: 296.149 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C14H11Cl2NO2 / Comment: antiinflammatory, inhibitor*YM
#6: 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-AKR / ACRYLIC ACID


Mass: 72.063 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C3H4O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 416 / 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: 2.76 Å3/Da / Density % sol: 55.4 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 34% PAA 5100, 100mM HEPES, 20mM MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.033 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 21, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.41→40 Å / Num. obs: 56332 / % possible obs: 98.6 % / Redundancy: 4.9 % / Net I/σ(I): 16

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.41→39.199 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 21.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2117 2780 5.21 %
Rwork0.1707 --
obs0.1728 53402 94.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.41→39.199 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8940 0 315 416 9671
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.019557
X-RAY DIFFRACTIONf_angle_d0.85412987
X-RAY DIFFRACTIONf_dihedral_angle_d14.123528
X-RAY DIFFRACTIONf_chiral_restr0.0361371
X-RAY DIFFRACTIONf_plane_restr0.0041665
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4096-2.45110.28521140.22162021X-RAY DIFFRACTION76
2.4511-2.49570.27121200.21252130X-RAY DIFFRACTION81
2.4957-2.54370.24611390.20412234X-RAY DIFFRACTION85
2.5437-2.59560.23631510.21522338X-RAY DIFFRACTION90
2.5956-2.6520.30481300.21412486X-RAY DIFFRACTION94
2.652-2.71370.2871480.21072559X-RAY DIFFRACTION98
2.7137-2.78150.2671210.20642646X-RAY DIFFRACTION99
2.7815-2.85670.28931250.21832652X-RAY DIFFRACTION99
2.8567-2.94070.26211350.19932647X-RAY DIFFRACTION99
2.9407-3.03560.22651650.18952622X-RAY DIFFRACTION99
3.0356-3.14410.21651460.19162588X-RAY DIFFRACTION99
3.1441-3.26990.18871720.18212632X-RAY DIFFRACTION99
3.2699-3.41860.24311530.18332629X-RAY DIFFRACTION99
3.4186-3.59880.19441610.15832600X-RAY DIFFRACTION99
3.5988-3.82410.15931250.14882647X-RAY DIFFRACTION98
3.8241-4.1190.19151280.14632642X-RAY DIFFRACTION98
4.119-4.5330.19031060.13642670X-RAY DIFFRACTION98
4.533-5.18760.1531890.12852679X-RAY DIFFRACTION97
5.1876-6.5310.17431760.16682582X-RAY DIFFRACTION96
6.531-39.2040.21521760.1722618X-RAY DIFFRACTION93
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)
12.4371-0.51530.37685.1263-1.18833.2048-0.15690.11930.0957-0.46770.24820.7984-0.0409-0.7731-0.09720.29190.047-0.0610.6431-0.03040.3813-1.256736.42326.5054
22.9957-0.78611.79432.61060.375.2056-0.00610.11050.4095-0.08440.01640.204-0.697-0.51370.03990.46820.1659-0.00610.42730.06560.510613.884663.424818.605
31.12690.3516-0.40561.0226-0.48532.2583-0.03750.2852-0.0881-0.1321-0.0433-0.01920.1309-0.20270.07110.26890.0332-0.02220.3511-0.03950.27623.171835.66518.7163
42.1895-0.20260.06350.480.20581.27670.03360.1610.01750.0218-0.1021-0.0526-0.09620.17870.06910.3223-0.0367-0.02160.30410.09350.360742.474450.236827.1329
51.04360.2349-0.00670.70580.13381.4018-0.04290.3940.0646-0.1615-0.03450.0176-0.0277-0.05930.0910.35490.0406-0.03240.39560.05790.315427.784846.162513.4356
63.0568-0.9762-0.81292.57730.11122.78890.1501-0.32720.71850.3355-0.10310.0046-0.55490.1029-0.04230.6646-0.0699-0.03620.3222-0.03720.520330.932266.635753.033
72.3453-0.0537-0.10432.03131.63584.73870.05780.00550.45960.1019-0.19010.2232-0.5939-0.28560.15260.51640.12550.01770.3463-0.06670.54424.056351.915361.288
80.78860.456-0.62990.9767-0.68912.89880.0509-0.30650.0340.2999-0.1906-0.1469-0.48170.35280.13610.3849-0.0708-0.05870.36520.01090.327735.737346.910159.3398
91.17090.3648-0.24230.8606-0.30351.2434-0.016-0.1345-0.22710.101-0.0635-0.08830.0237-0.02340.07720.2516-0.0056-0.00330.25030.01940.318418.258425.901655.8589
101.31390.47450.10220.6823-0.12210.96090.0722-0.32210.08190.2372-0.11260.0341-0.23490.09530.04210.3713-0.00360.00010.3315-0.02540.255921.317942.223363.9828
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 34:80)
2X-RAY DIFFRACTION2(chain A and resid 81:121)
3X-RAY DIFFRACTION3(chain A and resid 122:228)
4X-RAY DIFFRACTION4(chain A and resid 229:371)
5X-RAY DIFFRACTION5(chain A and resid 372:583)
6X-RAY DIFFRACTION6(chain B and resid 34:82)
7X-RAY DIFFRACTION7(chain B and resid 83:120)
8X-RAY DIFFRACTION8(chain B and resid 121:188)
9X-RAY DIFFRACTION9(chain B and resid 189:428)
10X-RAY DIFFRACTION10(chain B and resid 429:583)

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