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- PDB-4yl1: Crystal Structures of mPGES-1 Inhibitor Complexes -

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Basic information

Entry
Database: PDB / ID: 4yl1
TitleCrystal Structures of mPGES-1 Inhibitor Complexes
ComponentsProstaglandin E synthase
KeywordsISOMERASE/ISOMERASE INHIBITOR / Inhibitor / Inflammation / Prostaglandin / ISOMERASE-ISOMERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of fever generation / prostaglandin-E synthase / prostaglandin-E synthase activity / prostaglandin-D synthase activity / positive regulation of prostaglandin secretion / glutathione binding / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / glutathione peroxidase activity / prostaglandin biosynthetic process / prostaglandin metabolic process ...regulation of fever generation / prostaglandin-E synthase / prostaglandin-E synthase activity / prostaglandin-D synthase activity / positive regulation of prostaglandin secretion / glutathione binding / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / 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
Chem-4U8 / GLUTATHIONE / DI(HYDROXYETHYL)ETHER / Prostaglandin E synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.41 Å
AuthorsLuz, J.G. / Antonysamy, S. / Kuklish, S.L. / Fisher, M.J.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics.
Authors: Luz, J.G. / Antonysamy, S. / Kuklish, S.L. / Condon, B. / Lee, M.R. / Allison, D. / Yu, X.P. / Chandrasekhar, S. / Backer, R. / Zhang, A. / Russell, M. / Chang, S.S. / Harvey, A. / Sloan, A.V. / Fisher, M.J.
History
DepositionMar 4, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 8, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software / struct_keywords
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _software.classification / _struct_keywords.text
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / 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 / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Feb 28, 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

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Assembly

Deposited unit
A: Prostaglandin E synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,3067
Polymers16,6861
Non-polymers1,6206
Water2,108117
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)54,91721
Polymers50,0573
Non-polymers4,86018
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 area14520 Å2
ΔGint-44 kcal/mol
Surface area18790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.585, 76.585, 123.617
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-371-

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: 16685.785 Da / Num. of mol.: 1 / Fragment: residues 5-152
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
#5: 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, 121 molecules

#2: Chemical ChemComp-4U8 / 5-(4-tert-butylphenyl)-1-[4-(propan-2-yloxy)phenyl]-1H-indole-2-carboxylic acid


Mass: 427.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H29NO3
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-GSH / GLUTATHIONE


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


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / 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: 4.18 Å3/Da / Density % sol: 70.55 %
Crystal growTemperature: 294.15 K / Method: vapor diffusion, sitting drop / Details: 100mM Tris HCl pH 8.5 + 35% PEG 1K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.91986 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Apr 2, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91986 Å / Relative weight: 1
ReflectionResolution: 1.41→32 Å / Num. obs: 51297 / % possible obs: 99.4 % / Redundancy: 5.6 % / Net I/σ(I): 11.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
PDB_EXTRACT3.15data extraction
REFMACphasing
Cootmodel building
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.41→30 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.962 / SU B: 1.342 / SU ML: 0.023 / Cross valid method: THROUGHOUT / ESU R: 0.047 / ESU R Free: 0.043 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.1746 2601 5.1 %RANDOM
Rwork0.16274 ---
obs0.16334 48696 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.699 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20.03 Å2-0 Å2
2--0.07 Å2-0 Å2
3----0.21 Å2
Refinement stepCycle: LAST / Resolution: 1.41→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1174 0 108 117 1399
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0191367
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.992.0461859
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.7385157
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.83420.650
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.43215209
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1011512
X-RAY DIFFRACTIONr_chiral_restr0.0590.2210
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021997
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_it2.12228.827606
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.39445.32758
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.74639.346760
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.2052195
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr2.81531366
X-RAY DIFFRACTIONr_sphericity_free24.721529
X-RAY DIFFRACTIONr_sphericity_bonded12.13951414
LS refinement shellResolution: 1.415→1.452 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 185 -
Rwork0.348 3430 -
obs--95.96 %

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