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- PDB-2g0h: Structure-based drug design of a novel family of PPAR partial ago... -

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Basic information

Entry
Database: PDB / ID: 2g0h
TitleStructure-based drug design of a novel family of PPAR partial agonists: virtual screening, x-ray crystallography and in vitro/in vivo biological activities
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION ACTIVATOR / PPAR
Function / homology
Function and homology information


prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly / negative regulation of connective tissue replacement involved in inflammatory response wound healing / positive regulation of cholesterol transport / negative regulation of cellular response to transforming growth factor beta stimulus / negative regulation of cardiac muscle hypertrophy in response to stress / : ...prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly / negative regulation of connective tissue replacement involved in inflammatory response wound healing / positive regulation of cholesterol transport / negative regulation of cellular response to transforming growth factor beta stimulus / negative regulation of cardiac muscle hypertrophy in response to stress / : / arachidonate binding / positive regulation of adiponectin secretion / negative regulation of triglyceride storage / DNA binding domain binding / lipoprotein transport / positive regulation of vascular associated smooth muscle cell apoptotic process / STAT family protein binding / WW domain binding / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / LBD domain binding / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / lipid homeostasis / E-box binding / alpha-actinin binding / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of blood vessel endothelial cell migration / white fat cell differentiation / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / negative regulation of BMP signaling pathway / positive regulation of cholesterol efflux / negative regulation of mitochondrial fission / cell fate commitment / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / negative regulation of MAPK cascade / retinoic acid receptor signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / cell maturation / negative regulation of signaling receptor activity / positive regulation of adipose tissue development / hormone-mediated signaling pathway / epithelial cell differentiation / peroxisome proliferator activated receptor signaling pathway / response to nutrient / regulation of cellular response to insulin stimulus / negative regulation of miRNA transcription / peptide binding / negative regulation of angiogenesis / transcription coregulator binding / Regulation of PTEN gene transcription / fatty acid metabolic process / placenta development / positive regulation of apoptotic signaling pathway / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / mRNA transcription by RNA polymerase II / PPARA activates gene expression / regulation of circadian rhythm / lipid metabolic process / regulation of blood pressure / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / Nuclear Receptor transcription pathway / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / nuclear receptor activity / rhythmic process / glucose homeostasis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / double-stranded DNA binding / DNA-binding transcription activator activity, RNA polymerase II-specific / DNA-binding transcription factor binding / cellular response to hypoxia / sequence-specific DNA binding / nucleic acid binding / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / receptor complex / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / intracellular membrane-bounded organelle / innate immune response / negative regulation of DNA-templated transcription / positive regulation of gene expression / chromatin binding
Similarity search - Function
Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type ...Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / : / Retinoid X Receptor / Retinoid X Receptor / 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-SP3 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsLu, I.L. / Peng, Y.H. / Huang, C.F. / Lin, Y.T. / Hsu, J.T.A. / Wu, S.Y.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Structure-Based Drug Design of a Novel Family of PPARgamma Partial Agonists: Virtual Screening, X-ray Crystallography, and in Vitro/in Vivo Biological Activities
Authors: Lu, I.L. / Huang, C.F. / Peng, Y.H. / Lin, Y.T. / Hsieh, H.P. / Chen, C.T. / Lien, T.W. / Lee, H.J. / Mahindroo, N. / Prakash, E. / Yueh, A. / Chen, H.Y. / Goparaju, C.M. / Chen, X. / Liao, ...Authors: Lu, I.L. / Huang, C.F. / Peng, Y.H. / Lin, Y.T. / Hsieh, H.P. / Chen, C.T. / Lien, T.W. / Lee, H.J. / Mahindroo, N. / Prakash, E. / Yueh, A. / Chen, H.Y. / Goparaju, C.M. / Chen, X. / Liao, C.C. / Chao, Y.S. / Hsu, J.T. / Wu, S.Y.
History
DepositionFeb 13, 2006Deposition site: RCSB / Processing site: PDBJ
Revision 1.0May 16, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 25, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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 gamma
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,0654
Polymers61,9942
Non-polymers1,0712
Water1,56787
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.301, 88.897, 58.451
Angle α, β, γ (deg.)90.00, 90.80, 90.00
Int Tables number4
Space group name H-MP1211
DetailsThe second part of the biological assembly is generated by the two fold axis: -x, y+1/2, -z;

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Components

#1: Protein Peroxisome proliferator-activated receptor gamma / PPAR-gamma


Mass: 30997.021 Da / Num. of mol.: 2 / Fragment: Ligand binding domain(residues 207-477)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pGEX6P-1 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q86U60, UniProt: P37231*PLUS
#2: Chemical ChemComp-SP3 / N-[1-(4-FLUOROPHENYL)-3-(2-THIENYL)-1H-PYRAZOL-5-YL]-3,5-BIS(TRIFLUOROMETHYL)BENZENESULFONAMIDE


Mass: 535.458 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H12F7N3O2S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.36 Å3/Da / Density % sol: 47.85 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 20% PEG3350, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL12B2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: May 26, 2005
RadiationMonochromator: Monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→20 Å / Num. obs: 24250 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.3→2.359 Å / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
MOLREPphasing
REFMAC5refinement
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ATH

2ath


Resolution: 2.3→20 Å / σ(F): 3.78 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.293 1320 RANDOM
Rwork0.238 --
all0.241 --
obs0.238 24250 -
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4354 0 70 87 4511
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_refined_d0.008
X-RAY DIFFRACTIONr_angle_refined_deg1.796

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