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- PDB-8fhf: Crystal structure of PPARgamma ligand-binding domain in complex w... -

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Basic information

Entry
Database: PDB / ID: 8fhf
TitleCrystal structure of PPARgamma ligand-binding domain in complex with ZINC5672437
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / Nuclear receptors / TZDs / Drug design / Therapeutic targets / transcription-agonist complex
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
nonanoic acid / : / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsShang, J. / Kojetin, D.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)6R01DK124870 United States
CitationJournal: Nat Commun / Year: 2025
Title: Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.
Authors: MacTavish, B.S. / Zhu, D. / Shang, J. / Shao, Q. / He, Y. / Yang, Z.J. / Kamenecka, T.M. / Kojetin, D.J.
History
DepositionDec 14, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.2Apr 30, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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

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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)63,8556
Polymers62,8992
Non-polymers9564
Water4,648258
1
A: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9273
Polymers31,4501
Non-polymers4782
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9273
Polymers31,4501
Non-polymers4782
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)91.635, 60.695, 117.076
Angle α, β, γ (deg.)90.00, 102.51, 90.00
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: 31449.520 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pET46 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P37231
#2: Chemical ChemComp-XZK / N-(4-carbamoylphenyl)-2-chloro-5-nitrobenzamide


Mass: 319.700 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H10ClN3O4
#3: Chemical ChemComp-KNA / nonanoic acid


Mass: 158.238 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H18O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 258 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.53 Å3/Da / Density % sol: 51.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2M Ammonium sulfate, 0.1M MES, pH 6.5, 30% w/v, PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 26, 2019
RadiationMonochromator: Liquid nitrogen-cooled double crystal Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.1→38.89 Å / Num. obs: 35970 / % possible obs: 97.43 % / Redundancy: 2 % / Biso Wilson estimate: 21.52 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.01582 / Rpim(I) all: 0.01582 / Rrim(I) all: 0.02237 / Net I/σ(I): 16.87
Reflection shellResolution: 2.1→2.175 Å / Rmerge(I) obs: 0.2458 / Num. unique obs: 3565 / CC1/2: 0.961 / CC star: 0.99 / Rpim(I) all: 0.2458 / Rrim(I) all: 0.3477 / Χ2: 2.07

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Processing

Software
NameVersionClassification
SCALAdata scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
DIALSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→38.89 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.285 2000 5.57 %
Rwork0.2329 --
obs0.2358 35927 97.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→38.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4034 0 64 258 4356
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084316
X-RAY DIFFRACTIONf_angle_d1.0085799
X-RAY DIFFRACTIONf_dihedral_angle_d7.1742653
X-RAY DIFFRACTIONf_chiral_restr0.05663
X-RAY DIFFRACTIONf_plane_restr0.006735
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.15250.35821400.31922374X-RAY DIFFRACTION98
2.1525-2.21070.37951450.31092452X-RAY DIFFRACTION98
2.2107-2.27580.33641420.30112423X-RAY DIFFRACTION98
2.2758-2.34920.32361410.28972376X-RAY DIFFRACTION97
2.3492-2.43320.35831340.28422289X-RAY DIFFRACTION92
2.4332-2.53060.36481440.26932436X-RAY DIFFRACTION99
2.5306-2.64570.33861460.26752468X-RAY DIFFRACTION99
2.6457-2.78520.28991420.25172426X-RAY DIFFRACTION99
2.7852-2.95960.32111450.24672443X-RAY DIFFRACTION99
2.9596-3.1880.31450.24192474X-RAY DIFFRACTION99
3.188-3.50870.26271370.22042318X-RAY DIFFRACTION93
3.5087-4.01590.24261470.19182487X-RAY DIFFRACTION99
4.0159-5.05790.22991460.17742490X-RAY DIFFRACTION99
5.0579-38.890.22351460.18762471X-RAY DIFFRACTION96

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