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- PDB-4fm5: X-ray structure of des-methylflurbiprofen bound to murine COX-2 -

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Basic information

Entry
Database: PDB / ID: 4fm5
TitleX-ray structure of des-methylflurbiprofen bound to murine COX-2
ComponentsProstaglandin G/H synthase 2Cyclooxygenase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / membrane protein / cyclooxygenase / Heme binding / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


Biosynthesis of DHA-derived SPMs / Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 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 / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / hair cycle / Nicotinamide salvaging ...Biosynthesis of DHA-derived SPMs / Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 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 / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / hair cycle / Nicotinamide salvaging / 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 / 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 / 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 / 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 / keratinocyte differentiation / embryo implantation / positive regulation of brown fat cell differentiation / positive regulation of synaptic transmission, glutamatergic / learning / response to cytokine / caveola / peroxidase activity / positive regulation of smooth muscle cell proliferation / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / 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 cell population proliferation / cellular response to hypoxia / angiogenesis / response to oxidative stress / response to lipopolysaccharide / neuron projection / response to xenobiotic stimulus / positive regulation of apoptotic process / negative regulation of cell population proliferation / positive regulation of cell population proliferation / heme binding / endoplasmic reticulum membrane / negative regulation of apoptotic process / 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
(2-fluorobiphenyl-4-yl)acetic acid / PROTOPORPHYRIN IX CONTAINING FE / Prostaglandin G/H synthase 2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsXu, S. / Banerjee, S. / Windsor, M.A. / Marnett, L.J.
CitationJournal: ACS Med Chem Lett / Year: 2012
Title: Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes.
Authors: Windsor, M.A. / Hermanson, D.J. / Kingsley, P.J. / Xu, S. / Crews, B.C. / Ho, W. / Keenan, C.M. / Banerjee, S. / Sharkey, K.A. / Marnett, L.J.
History
DepositionJun 15, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 19, 2012Group: Database references
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.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_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.value / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_atom_id_1 / _pdbx_validate_close_contact.auth_atom_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _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 2.1Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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
C: Prostaglandin G/H synthase 2
D: Prostaglandin G/H synthase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)283,21022
Polymers276,3724
Non-polymers6,83918
Water3,351186
1
A: Prostaglandin G/H synthase 2
B: Prostaglandin G/H synthase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,60511
Polymers138,1862
Non-polymers3,4199
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12060 Å2
ΔGint-14 kcal/mol
Surface area42500 Å2
MethodPISA
2
C: Prostaglandin G/H synthase 2
D: Prostaglandin G/H synthase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,60511
Polymers138,1862
Non-polymers3,4199
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12070 Å2
ΔGint-13 kcal/mol
Surface area42560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)181.632, 135.696, 125.150
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.999611, -0.020025, -0.019422), (-0.020518, 0.056091, 0.998215), (-0.0189, 0.998225, -0.05648)82.99772, 33.57566, -33.75602

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Prostaglandin G/H synthase 2 / Cyclooxygenase / Cyclooxygenase-2 / COX-2 / Glucocorticoid-regulated inflammatory cyclooxygenase / Gripghs / ...Cyclooxygenase-2 / COX-2 / Glucocorticoid-regulated inflammatory cyclooxygenase / Gripghs / Macrophage activation-associated marker protein P71/73 / PES-2 / PHS II / Prostaglandin H2 synthase 2 / PGH synthase 2 / PGHS-2 / Prostaglandin-endoperoxide synthase 2 / TIS10 protein


Mass: 69092.914 Da / Num. of mol.: 4 / Fragment: Prostaglandin G/H synthase 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ptgs2, Cox-2, Cox2, Pghs-b, Tis10 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q05769, prostaglandin-endoperoxide synthase

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Sugars , 2 types, 10 molecules

#2: 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.: 4
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
#3: Sugar
ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside / Octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 6
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 , 3 types, 194 molecules

#4: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#5: Chemical
ChemComp-DF0 / (2-fluorobiphenyl-4-yl)acetic acid / Des-methylflurbiprofen


Mass: 230.234 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H11FO2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 186 / 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: 2.79 Å3/Da / Density % sol: 55.92 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 50 mM EPPS pH 8.0, 20~25% PEG MME 550, 80~120 mM MgCl2, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97929 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 12, 2012
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 74531 / % possible obs: 98.46 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.1 % / Biso Wilson estimate: 48.97 Å2 / Rmerge(I) obs: 0.158 / Rsym value: 0.094 / Net I/σ(I): 6.92
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 4 % / Rmerge(I) obs: 0.842 / Mean I/σ(I) obs: 2.03 / Num. unique all: 7384 / Rsym value: 0.498 / % possible all: 81.56

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.6.0117refinement
HKL-2000data reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NT1

3nt1


Resolution: 2.81→49.86 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.882 / SU B: 17.009 / SU ML: 0.324 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R Free: 0.429 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28974 3752 5 %RANDOM
Rwork0.24035 ---
obs0.24279 70778 98.46 %-
all-75431 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.877 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å20 Å20 Å2
2--0.1 Å2-0 Å2
3---0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.81→49.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17896 0 472 186 18554
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0219084
X-RAY DIFFRACTIONr_bond_other_d0.0080.0213140
X-RAY DIFFRACTIONr_angle_refined_deg1.9841.99325932
X-RAY DIFFRACTIONr_angle_other_deg1.4693.00331864
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.32652204
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.37424.107896
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.641153104
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5881592
X-RAY DIFFRACTIONr_chiral_restr0.1170.22748
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02120828
X-RAY DIFFRACTIONr_gen_planes_other0.0070.023988
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
2.81-2.910.40213370.3651618286.9
2.91-3.030.39073740.3386706099.8
3.03-3.160.36833680.2996708399.9
3.16-3.340.33583920.27737106100
3.34-3.540.31153730.249714999.9
3.54-3.820.29283910.2511711199.8
3.82-4.20.25453600.1953719399.8
4.2-4.810.24373770.187717799.6
4.81-6.060.24763830.2121723199.2
6.06-460.29123970.26374089738998.2

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