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- PDB-3fei: Design and biological evaluation of novel, balanced dual PPARa/g ... -

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Basic information

Entry
Database: PDB / ID: 3fei
TitleDesign and biological evaluation of novel, balanced dual PPARa/g agonists
Components
  • Peptide motif 5 of Nuclear receptor coactivator 1
  • Peroxisome proliferator-activated receptor alpha
KeywordsTRANSCRIPTION / NUCLEAR RECEPTOR / TRANSCRIPTION FACTOR / DIABETES / Activator / DNA-binding / Metal-binding / Nucleus / Polymorphism / Receptor / Transcription regulation / Zinc / Zinc-finger
Function / homology
Function and homology information


positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / regulation of ketone metabolic process / regulation of fatty acid metabolic process / cellular response to fructose stimulus / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / behavioral response to nicotine ...positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / regulation of ketone metabolic process / regulation of fatty acid metabolic process / cellular response to fructose stimulus / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / behavioral response to nicotine / lipoprotein metabolic process / positive regulation of fatty acid oxidation / negative regulation of hepatocyte apoptotic process / negative regulation of leukocyte cell-cell adhesion / mitogen-activated protein kinase kinase kinase binding / labyrinthine layer morphogenesis / positive regulation of transcription from RNA polymerase II promoter by galactose / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / ubiquitin conjugating enzyme binding / negative regulation of glycolytic process / negative regulation of triglyceride storage / nuclear steroid receptor activity / nitric oxide metabolic process / DNA-binding transcription activator activity / positive regulation of fatty acid metabolic process / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / hypothalamus development / positive regulation of ATP biosynthetic process / NFAT protein binding / negative regulation of cholesterol storage / cellular response to Thyroglobulin triiodothyronine / negative regulation of macrophage derived foam cell differentiation / Synthesis of bile acids and bile salts / negative regulation of cytokine production involved in inflammatory response / epidermis development / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / phosphatase binding / nuclear retinoid X receptor binding / progesterone receptor signaling pathway / response to retinoic acid / positive regulation of lipid biosynthetic process / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / histone H4K16 acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K4 acetyltransferase activity / histone H3K27 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K122 acetyltransferase activity / histone H3K18 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K12 acetyltransferase activity / cellular response to hormone stimulus / estrous cycle / Recycling of bile acids and salts / histone acetyltransferase / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / negative regulation of blood pressure / negative regulation of signaling receptor activity / negative regulation of reactive oxygen species biosynthetic process / estrogen receptor signaling pathway / positive regulation of adipose tissue development / : / hormone-mediated signaling pathway / MDM2/MDM4 family protein binding / lactation / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / response to nutrient / positive regulation of gluconeogenesis / regulation of cellular response to insulin stimulus / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cerebellum development / positive regulation of neuron differentiation / BMAL1:CLOCK,NPAS2 activates circadian expression / negative regulation of miRNA transcription / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / : / cellular response to starvation / hippocampus development / response to progesterone / nuclear receptor binding / gluconeogenesis / fatty acid metabolic process / nuclear estrogen receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / response to insulin / SUMOylation of intracellular receptors
Similarity search - Function
Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain ...Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / Nuclear receptor coactivator, interlocking / : / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / PAS domain superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-CTM / Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsBenz, J. / Grether, U. / Gsell, B. / Binggeli, A. / Hilpert, H. / Maerki, H.P. / Mohr, P. / Ruf, A. / Stihle, M. / Schlatter, D.
CitationJournal: Chemmedchem / Year: 2009
Title: Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists
Authors: Grether, U. / Benardeau, A. / Benz, J. / Binggeli, A. / Blum, D. / Hilpert, H. / Kuhn, B. / Maerki, H.P. / Meyer, M. / Mohr, P. / Puntener, K. / Raab, S. / Ruf, A. / Schlatter, D.
History
DepositionNov 30, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 20, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Peroxisome proliferator-activated receptor alpha
Z: Peptide motif 5 of Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3633
Polymers31,9312
Non-polymers4321
Water2,540141
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1130 Å2
ΔGint-9 kcal/mol
Surface area12240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.528, 75.705, 97.891
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Peroxisome proliferator-activated receptor alpha / PPAR-alpha / Nuclear receptor subfamily 1 group C member 1


Mass: 30270.402 Da / Num. of mol.: 1 / Fragment: PPARalpha ligand binding domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARA, NR1C1, PPAR / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / References: UniProt: Q07869
#2: Protein/peptide Peptide motif 5 of Nuclear receptor coactivator 1 / SRC-1 Coactivator protein motif 5


Mass: 1660.912 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Chemically synthesis / References: UniProt: Q15788
#3: Chemical ChemComp-CTM / (2S)-3-(4-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy}-2-methylphenyl)-2-ethoxypropanoic acid / 3-{4-[2-(4-Chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-(S)-ethoxy-propionic acid


Mass: 431.932 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22ClNO4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 141 / 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: 2.47 Å3/Da / Density % sol: 50.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.1M Tris, 0.2M MgCl2, 25% PEG3350, 15% Glycerol, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9184 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Aug 1, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 12953 / % possible obs: 100 % / Biso Wilson estimate: 54.3 Å2 / Rsym value: 0.066 / Net I/σ(I): 25.2
Reflection shellResolution: 2.4→2.49 Å / Mean I/σ(I) obs: 5.2 / Num. unique all: 1276 / Rsym value: 0.345 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.4→30 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.934 / SU B: 9.649 / SU ML: 0.225 / Cross valid method: THROUGHOUT / ESU R: 0.425 / ESU R Free: 0.269 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25972 630 4.9 %RANDOM
Rwork0.21653 ---
obs0.21867 12282 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 52.921 Å2
Baniso -1Baniso -2Baniso -3
1--0.29 Å20 Å20 Å2
2---4.88 Å20 Å2
3---5.17 Å2
Refinement stepCycle: LAST / Resolution: 2.4→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2043 0 29 141 2213
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222111
X-RAY DIFFRACTIONr_angle_refined_deg1.3151.9922842
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1855250
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.74824.52695
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.58715393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.3191510
X-RAY DIFFRACTIONr_chiral_restr0.0850.2323
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021548
X-RAY DIFFRACTIONr_nbd_refined0.2070.21009
X-RAY DIFFRACTIONr_nbtor_refined0.2990.21439
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1970.2150
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1720.226
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1380.23
X-RAY DIFFRACTIONr_mcbond_it0.6721.51316
X-RAY DIFFRACTIONr_mcangle_it1.18722043
X-RAY DIFFRACTIONr_scbond_it1.5143934
X-RAY DIFFRACTIONr_scangle_it2.4454.5799
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.482 47 -
Rwork0.281 882 -
obs--99.25 %

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