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- PDB-8dsy: PPARg bound to inverse agonist H3B-343 -

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Basic information

Entry
Database: PDB / ID: 8dsy
TitlePPARg bound to inverse agonist H3B-343
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsNUCLEAR PROTEIN / PPARg / inverse agonist / H3B-343
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 / : / arachidonate binding ...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 / : / arachidonate binding / positive regulation of adiponectin secretion / negative regulation of cardiac muscle hypertrophy in response to stress / DNA binding domain binding / lipoprotein transport / positive regulation of vascular associated smooth muscle cell apoptotic process / WW domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / 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 / negative regulation of MAPK cascade / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / retinoic acid receptor signaling pathway / cell maturation / intracellular receptor signaling pathway / positive regulation of adipose tissue development / hormone-mediated signaling pathway / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / response to nutrient / negative regulation of miRNA transcription / peptide binding / negative regulation of angiogenesis / transcription coregulator binding / positive regulation of apoptotic signaling pathway / Regulation of PTEN gene transcription / fatty acid metabolic process / placenta development / 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 / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / regulation of blood pressure / lipid metabolic process / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / 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 / DNA-binding transcription activator activity, RNA polymerase II-specific / double-stranded DNA binding / 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 / innate immune response / negative regulation of gene expression / negative regulation of DNA-templated transcription / intracellular membrane-bounded organelle / chromatin binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II
Similarity search - Function
Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated 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. ...Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated 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
Similarity search - Domain/homology
Chem-TJC / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsLarsen, N.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Biol.Chem. / Year: 2022
Title: Biochemical and structural basis for the pharmacological inhibition of nuclear hormone receptor PPAR gamma by inverse agonists.
Authors: Irwin, S. / Karr, C. / Furman, C. / Tsai, J. / Gee, P. / Banka, D. / Wibowo, A.S. / Dementiev, A.A. / O'Shea, M. / Yang, J. / Lowe, J. / Mitchell, L. / Ruppel, S. / Fekkes, P. / Zhu, P. / ...Authors: Irwin, S. / Karr, C. / Furman, C. / Tsai, J. / Gee, P. / Banka, D. / Wibowo, A.S. / Dementiev, A.A. / O'Shea, M. / Yang, J. / Lowe, J. / Mitchell, L. / Ruppel, S. / Fekkes, P. / Zhu, P. / Korpal, M. / Larsen, N.A.
History
DepositionJul 24, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 7, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)63,3684
Polymers62,3022
Non-polymers1,0662
Water55831
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.758, 63.503, 118.333
Angle α, β, γ (deg.)90.000, 101.400, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 31151.186 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Production host: Escherichia coli (E. coli) / References: UniProt: P37231
#2: Chemical ChemComp-TJC / {5-[(5-{[(4-tert-butylphenyl)methyl]carbamoyl}-2,3-dimethyl-1H-indol-1-yl)methyl]-2-chlorophenoxy}acetic acid


Mass: 533.058 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H33ClN2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.71 Å3/Da / Density % sol: 54.65 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop
Details: 2+2 uL drops of protein + reservoir consisting of 0.9-1.2 M Na citrate and 100 mM Tris pH 8.0. Protein formulated at 20 mg mL-1 in 20 mM Tris, pH 8.0, 100 mM NaCl, and 1mM TCEP

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Data collection

DiffractionMean temperature: 120 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.9786 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Aug 20, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.95→50 Å / Num. obs: 14263 / % possible obs: 99.9 % / Redundancy: 5 % / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.044 / Rrim(I) all: 0.098 / Χ2: 1.312 / Net I/σ(I): 8.8 / Num. measured all: 70991
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.95-34.60.9616790.7480.5061.091.19799.3
3-3.064.80.8327050.8440.4230.9361.16199.7
3.06-3.1150.7787190.8790.390.8721.223100
3.11-3.1850.6076870.870.3050.681.226100
3.18-3.2550.4947170.9180.2460.5521.27100
3.25-3.3250.3747030.9590.1870.4191.359100
3.32-3.415.10.3067160.9630.1520.3431.255100
3.41-3.55.10.2587220.9750.1280.2891.354100
3.5-3.65.10.2076910.9820.1030.2311.334100
3.6-3.725.10.1677330.9860.0830.1871.367100
3.72-3.855.10.1236920.9920.0610.1371.426100
3.85-45.10.1067270.9940.0530.1191.377100
4-4.1950.0797010.9960.0390.0881.467100
4.19-4.415.10.077180.9970.0350.0791.417100
4.41-4.685.10.0637120.9980.0310.071.383100
4.68-5.045.10.0577200.9970.0280.0641.298100
5.04-5.5550.0587230.9980.0290.0661.364100
5.55-6.3550.067160.9970.030.0671.283100
6.35-84.90.0377400.9990.0190.0421.23100
8-504.60.0257420.9990.0130.0291.21899.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
SCALEPACKdata scaling
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PRG

2prg


Resolution: 2.95→49.51 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.921 / SU B: 22.672 / SU ML: 0.406 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.45 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2669 988 6.9 %RANDOM
Rwork0.1982 ---
obs0.2032 13274 99.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 182.59 Å2 / Biso mean: 81.367 Å2 / Biso min: 30 Å2
Baniso -1Baniso -2Baniso -3
1--0.09 Å20 Å20.05 Å2
2---0.11 Å2-0 Å2
3---0.17 Å2
Refinement stepCycle: final / Resolution: 2.95→49.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4019 0 76 31 4126
Biso mean--81.33 60.02 -
Num. residues----519
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194170
X-RAY DIFFRACTIONr_bond_other_d0.0030.023902
X-RAY DIFFRACTIONr_angle_refined_deg1.472.0055662
X-RAY DIFFRACTIONr_angle_other_deg1.033.0059010
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3395514
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.53425.198177
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.615706
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.6781515
X-RAY DIFFRACTIONr_chiral_restr0.0730.2663
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214583
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02804
LS refinement shellResolution: 2.95→3.021 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.358 72 -
Rwork0.355 899 -
obs--92.92 %

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