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- PDB-5bqh: Discovery of a Potent and Selective mPGES-1 Inhibitor for the Tre... -

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Basic information

Entry
Database: PDB / ID: 5bqh
TitleDiscovery of a Potent and Selective mPGES-1 Inhibitor for the Treatment of Pain
ComponentsProstaglandin E synthase
KeywordsIsomerase/isomerase inhibitor / mPGES-1 / enzyme / integral membrane protein / Isomerase-isomerase inhibitor complex
Function / homology
Function and homology information


prostaglandin-E synthase / prostaglandin-E synthase activity / regulation of fever generation / prostaglandin-D synthase activity / glutathione binding / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / positive regulation of prostaglandin secretion / glutathione peroxidase activity / prostaglandin biosynthetic process / prostaglandin metabolic process ...prostaglandin-E synthase / prostaglandin-E synthase activity / regulation of fever generation / prostaglandin-D synthase activity / glutathione binding / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / positive regulation of prostaglandin secretion / glutathione peroxidase activity / prostaglandin biosynthetic process / prostaglandin metabolic process / nuclear envelope lumen / glutathione transferase / glutathione transferase activity / Oxidoreductases; Acting on a peroxide as acceptor; Peroxidases / sensory perception of pain / regulation of inflammatory response / cell population proliferation / negative regulation of cell population proliferation / endoplasmic reticulum membrane / perinuclear region of cytoplasm / signal transduction / membrane
Similarity search - Function
Microsomal glutathione S-transferase 1-like / Membrane associated eicosanoid/glutathione metabolism-like domain / Membrane-associated, eicosanoid/glutathione metabolism (MAPEG) protein / Membrane associated eicosanoid/glutathione metabolism-like domain superfamily / MAPEG family / Four Helix Bundle (Hemerythrin (Met), subunit A) / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
(2-hydroxyethoxy)acetaldehyde / Chem-4UK / GLUTATHIONE / Prostaglandin E synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.601 Å
AuthorsFisher, M.J. / Schiffler, M.A. / Kuklish, S.L. / Antonysamy, S. / Luz, J.G.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.
Authors: Schiffler, M.A. / Antonysamy, S. / Bhattachar, S.N. / Campanale, K.M. / Chandrasekhar, S. / Condon, B. / Desai, P.V. / Fisher, M.J. / Groshong, C. / Harvey, A. / Hickey, M.J. / Hughes, N.E. ...Authors: Schiffler, M.A. / Antonysamy, S. / Bhattachar, S.N. / Campanale, K.M. / Chandrasekhar, S. / Condon, B. / Desai, P.V. / Fisher, M.J. / Groshong, C. / Harvey, A. / Hickey, M.J. / Hughes, N.E. / Jones, S.A. / Kim, E.J. / Kuklish, S.L. / Luz, J.G. / Norman, B.H. / Rathmell, R.E. / Rizzo, J.R. / Seng, T.W. / Thibodeaux, S.J. / Woods, T.A. / York, J.S. / Yu, X.P.
History
DepositionMay 29, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / citation ...chem_comp / citation / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_struct_oper_list / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.name ..._chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _citation.journal_id_CSD / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_oper_list.symmetry_operation
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
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 E synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,9457
Polymers17,3081
Non-polymers1,6376
Water2,216123
1
A: Prostaglandin E synthase
hetero molecules

A: Prostaglandin E synthase
hetero molecules

A: Prostaglandin E synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,83421
Polymers51,9233
Non-polymers4,91218
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area13690 Å2
ΔGint-54 kcal/mol
Surface area19210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.464, 76.464, 123.770
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11A-379-

HOH

21A-404-

HOH

31A-423-

HOH

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Components

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Protein / Sugars , 2 types, 3 molecules A

#1: Protein Prostaglandin E synthase / Microsomal glutathione S-transferase 1-like 1 / MGST1-L1 / Microsomal prostaglandin E synthase 1 / ...Microsomal glutathione S-transferase 1-like 1 / MGST1-L1 / Microsomal prostaglandin E synthase 1 / MPGES-1 / p53-induced gene 12 protein


Mass: 17307.559 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTGES, MGST1L1, MPGES1, PGES, PIG12 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O14684, prostaglandin-E synthase
#4: 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.: 2
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 , 5 types, 127 molecules

#2: Chemical ChemComp-4UK / N-[4-(4-chlorophenyl)-1H-imidazol-2-yl]-2-(difluoromethyl)-5-{[(2-methylpropanoyl)amino]methyl}benzamide


Mass: 446.878 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21ClF2N4O2
#3: Chemical ChemComp-GSH / GLUTATHIONE


Mass: 307.323 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N3O6S
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Chemical ChemComp-1KA / (2-hydroxyethoxy)acetaldehyde


Mass: 104.105 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 4.02 Å3/Da / Density % sol: 69.43 %
Crystal growTemperature: 294.15 K / Method: vapor diffusion, sitting drop / Details: 100mM Tris HCl pH 9.2 + 32% PEG 1K

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Data collection

DiffractionMean temperature: 93.15 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Oct 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 1.6→30 Å / Num. obs: 33609 / % possible obs: 99.6 % / Redundancy: 5.6 % / Net I/σ(I): 9.1
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 3.1 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementResolution: 1.601→30 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.957 / SU B: 2.22 / SU ML: 0.035 / Cross valid method: THROUGHOUT / ESU R: 0.064 / ESU R Free: 0.056 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.16538 1770 5 %RANDOM
Rwork0.14495 ---
obs0.14598 33609 99.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.692 Å2
Baniso -1Baniso -2Baniso -3
1-0.2 Å20.1 Å2-0 Å2
2--0.2 Å2-0 Å2
3----0.66 Å2
Refinement stepCycle: 1 / Resolution: 1.601→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1171 0 111 123 1405
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0191394
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.9532.0091899
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.6655164
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.97320.76952
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.0115209
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8451512
X-RAY DIFFRACTIONr_chiral_restr0.0580.2212
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211032
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.11128.828621
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.12545.097781
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it6.81141.426772
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.6332232
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr1.93431393
X-RAY DIFFRACTIONr_sphericity_free23.219539
X-RAY DIFFRACTIONr_sphericity_bonded14.2151435
LS refinement shellResolution: 1.601→1.643 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.24 147 -
Rwork0.214 2472 -
obs--100 %

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