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- PDB-3et3: Structure of PPARgamma with 3-[5-Methoxy-1-(4-methoxy-benzenesulf... -

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Basic information

Entry
Database: PDB / ID: 3et3
TitleStructure of PPARgamma with 3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid
Components
  • Peroxisome proliferator-activated receptor gamma
  • Steroid receptor coactivator 1Nuclear receptor coactivator 1
KeywordsTRANSCRIPTION / PPAR / PPARg / PPARgamma / Drug Discovery / Diabetes / adiponectin / metabolic disease / fragment-based drug discovery / scaffold-based drug discovery / Activator / Alternative splicing / Diabetes mellitus / Disease mutation / DNA-binding / Metal-binding / Nucleus / Obesity / Phosphoprotein / Polymorphism / Receptor / Transcription regulation / Zinc / Zinc-finger / Acyltransferase / Chromosomal rearrangement / Proto-oncogene / Transferase / Ubl conjugation
Function / homology
Function and homology information


labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / prostaglandin receptor activity / regulation of cholesterol transporter activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / positive regulation of female receptivity / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly ...labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / prostaglandin receptor activity / regulation of cholesterol transporter activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / positive regulation of female receptivity / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation / negative regulation of cellular response to transforming growth factor beta stimulus / negative regulation of cardiac muscle hypertrophy in response to stress / arachidonic acid binding / positive regulation of low-density lipoprotein receptor activity / positive regulation of adiponectin secretion / lipoprotein transport / negative regulation of sequestering of triglyceride / positive regulation of vascular associated smooth muscle cell apoptotic process / hypothalamus development / macrophage derived foam cell differentiation / DNA binding domain binding / male mating behavior / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of SMAD protein signal transduction / LBD domain binding / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / E-box binding / alpha-actinin binding / negative regulation of blood vessel endothelial cell migration / lipid homeostasis / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / estrous cycle / positive regulation of cholesterol efflux / cellular response to low-density lipoprotein particle stimulus / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / cellular response to Thyroglobulin triiodothyronine / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / Synthesis of bile acids and bile salts / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / long-chain fatty acid transport / retinoic acid receptor signaling pathway / positive regulation of DNA binding / cell fate commitment / Endogenous sterols / BMP signaling pathway / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to retinoic acid / negative regulation of signaling receptor activity / histone acetyltransferase activity / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / cell maturation / histone acetyltransferase / cellular response to hormone stimulus / positive regulation of adipose tissue development / epithelial cell differentiation / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / positive regulation of neuron differentiation / lactation / Regulation of lipid metabolism by PPARalpha / cerebellum development / hormone-mediated signaling pathway / negative regulation of angiogenesis / response to nutrient / negative regulation of MAP kinase activity / fatty acid metabolic process / BMAL1:CLOCK,NPAS2 activates circadian gene expression / nuclear receptor coactivator activity / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / negative regulation of miRNA transcription / response to progesterone / placenta development / Regulation of PTEN gene transcription / negative regulation of smooth muscle cell proliferation / nuclear estrogen receptor binding / transcription coregulator binding / nuclear receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / negative regulation of transforming growth factor beta receptor signaling pathway / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II
Similarity search - Function
Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / 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 ...Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / 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 DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / 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-ET1 / Peroxisome proliferator-activated receptor gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsZhang, K.Y.J. / Wang, W.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2009
Title: Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent
Authors: Artis, D.R. / Lin, J.J. / Zhang, C. / Wang, W. / Mehra, U. / Perreault, M. / Erbe, D. / Krupka, H.I. / England, B.P. / Arnold, J. / Plotnikov, A.N. / Marimuthu, A. / Nguyen, H. / Will, S. / ...Authors: Artis, D.R. / Lin, J.J. / Zhang, C. / Wang, W. / Mehra, U. / Perreault, M. / Erbe, D. / Krupka, H.I. / England, B.P. / Arnold, J. / Plotnikov, A.N. / Marimuthu, A. / Nguyen, H. / Will, S. / Signaevsky, M. / Kral, J. / Cantwell, J. / Settachatgull, C. / Yan, D.S. / Fong, D. / Oh, A. / Shi, S. / Womack, P. / Powell, B. / Habets, G. / West, B.L. / Zhang, K.Y. / Milburn, M.V. / Vlasuk, G.P. / Hirth, K.P. / Nolop, K. / Bollag, G. / Ibrahim, P.N. / Tobin, J.F.
History
DepositionOct 6, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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
P: Steroid receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6633
Polymers35,2742
Non-polymers3891
Water3,909217
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1340 Å2
ΔGint-10 kcal/mol
Surface area13440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.853, 86.671, 122.135
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Peroxisome proliferator-activated receptor gamma / / PPAR-gamma / Nuclear receptor subfamily 1 group C member 3


Mass: 33299.570 Da / Num. of mol.: 1 / Fragment: LIGAND BINDING DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pET-28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)RIL / References: UniProt: P37231
#2: Protein/peptide Steroid receptor coactivator 1 / Nuclear receptor coactivator 1 / NCoA-1 / Nuclear receptor coactivator 1 / SRC-1 / RIP160 / Protein Hin-2 / Renal carcinoma antigen NY-REN-52


Mass: 1974.314 Da / Num. of mol.: 1 / Fragment: residues 681-696
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOA1, SRC1 / Plasmid: pET-28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)RIL / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-ET1 / 3-{5-methoxy-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-3-yl}propanoic acid


Mass: 389.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19NO6S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 1.98 Å3/Da / Density % sol: 37.96 %
Crystal growTemperature: 277 K / pH: 6.5
Details: The purified PPARg LBD protein was diluted to 12 mg/ml and 1mM of indeglitazar and 2x molar excess of SRC-1 peptide were added prior to crystallization by mixing equal volumes of ...Details: The purified PPARg LBD protein was diluted to 12 mg/ml and 1mM of indeglitazar and 2x molar excess of SRC-1 peptide were added prior to crystallization by mixing equal volumes of protein/compound sample with reservoir solution containing 27% polyethylene glycol (PEG) 4000, 0.1 M 2-(bis-(2-hydroxy-ethyl)-amino)-2-hydroxymethyl- propane-1,3-diol (BisTris) buffer at pH 6.5, 0.2 M ammonium acetate, and 5% glycerol, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: May 11, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 1.95→61.1 Å / Num. obs: 22003 / % possible obs: 97.8 % / Observed criterion σ(I): 0 / Redundancy: 4.5 % / Rsym value: 0.051
Reflection shellResolution: 1.95→2 Å / Redundancy: 4.7 % / Mean I/σ(I) obs: 1.8 / Rsym value: 0.288 / % possible all: 99.2

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Processing

Software
NameClassification
Blu-Icedata collection
CCP4model building
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2PRG

2prg


Resolution: 1.95→61.07 Å / SU ML: 0.29 / σ(F): 1.34 / Phase error: 23.31 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.236 1065 5.23 %
Rwork0.179 --
obs0.182 20354 97.7 %
all-20842 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 64.68 Å2 / ksol: 0.34 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--1.2466 Å20 Å2-0 Å2
2--9.1063 Å2-0 Å2
3----7.8597 Å2
Refinement stepCycle: LAST / Resolution: 1.95→61.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2223 0 27 217 2467
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062288
X-RAY DIFFRACTIONf_angle_d0.9243083
X-RAY DIFFRACTIONf_dihedral_angle_d15.033878
X-RAY DIFFRACTIONf_chiral_restr0.065354
X-RAY DIFFRACTIONf_plane_restr0.003387
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-2.03880.25841150.21182428X-RAY DIFFRACTION99
2.0388-2.14630.27221470.18592364X-RAY DIFFRACTION99
2.1463-2.28070.25041460.18252402X-RAY DIFFRACTION99
2.2807-2.45680.27261290.17912410X-RAY DIFFRACTION99
2.4568-2.70410.25121250.19242423X-RAY DIFFRACTION98
2.7041-3.09540.2611380.19522424X-RAY DIFFRACTION98
3.0954-3.89970.23891420.16952416X-RAY DIFFRACTION97
3.8997-61.09740.19231230.16532422X-RAY DIFFRACTION93
Refinement TLS params.Method: refined / Origin x: 30.4425 Å / Origin y: 32.9042 Å / Origin z: 75.7804 Å
111213212223313233
T0.2289 Å2-0.0261 Å2-0.0158 Å2-0.2043 Å20.0034 Å2--0.1841 Å2
L1.4539 °20.3174 °20.2746 °2-1.9586 °20.675 °2--2.3477 °2
S-0.0456 Å °0.1589 Å °0.0003 Å °-0.1759 Å °0.1263 Å °0.041 Å °0.2135 Å °0.1915 Å °-0 Å °
Refinement TLS groupSelection details: CHAIN A

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