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- PDB-6f2l: Crystal structure of the complex between PPARgamma LBD and the li... -

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Basic information

Entry
Database: PDB / ID: 6f2l
TitleCrystal structure of the complex between PPARgamma LBD and the ligand LJ570: structure obtained from crystals of the apo-form soaked for 15 days.
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / nuclear receptor / transcription factor / complex with an agonist
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 / lipoprotein transport / DNA binding domain binding / negative regulation of cardiac muscle hypertrophy in response to stress / positive regulation of vascular associated smooth muscle cell apoptotic process / WW domain binding / positive regulation of fatty acid metabolic process / STAT family protein binding / 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 / R-SMAD binding / negative regulation of vascular associated smooth muscle cell proliferation / 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 / positive regulation of cholesterol efflux / negative regulation of BMP signaling pathway / cell fate commitment / negative regulation of osteoblast differentiation / negative regulation of mitochondrial fission / positive regulation of fat cell differentiation / 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 / negative regulation of MAPK cascade / intracellular receptor signaling pathway / hormone-mediated signaling pathway / positive regulation of adipose tissue development / response to nutrient / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / peptide binding / negative regulation of miRNA transcription / negative regulation of angiogenesis / placenta development / Regulation of PTEN gene transcription / positive regulation of apoptotic signaling pathway / transcription coregulator binding / negative regulation of smooth muscle cell proliferation / SUMOylation of intracellular receptors / negative regulation of transforming growth factor beta receptor signaling pathway / mRNA transcription by RNA polymerase II / fatty acid metabolic process / PPARA activates gene expression / regulation of circadian rhythm / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / lipid metabolic process / regulation of blood pressure / positive regulation of miRNA transcription / 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 / cellular response to hypoxia / DNA-binding transcription factor binding / 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 / innate immune response / 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 / : / 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-AXY / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsPochetti, G. / Montanari, M.
Citation
Journal: J.Med.Chem. / Year: 2018
Title: Identification of the First PPAR alpha / gamma Dual Agonist Able To Bind to Canonical and Alternative Sites of PPAR gamma and To Inhibit Its Cdk5-Mediated Phosphorylation.
Authors: Laghezza, A. / Piemontese, L. / Cerchia, C. / Montanari, R. / Capelli, D. / Giudici, M. / Crestani, M. / Tortorella, P. / Peiretti, F. / Pochetti, G. / Lavecchia, A. / Loiodice, F.
#1: Journal: J. Med. Chem. / Year: 2008
Title: Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could ...Title: Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design.
Authors: Montanari, R. / Saccoccia, F. / Scotti, E. / Crestani, M. / Godio, C. / Gilardi, F. / Loiodice, F. / Fracchiolla, G. / Laghezza, A. / Tortorella, P. / Lavecchia, A. / Novellino, E. / Mazza, ...Authors: Montanari, R. / Saccoccia, F. / Scotti, E. / Crestani, M. / Godio, C. / Gilardi, F. / Loiodice, F. / Fracchiolla, G. / Laghezza, A. / Tortorella, P. / Lavecchia, A. / Novellino, E. / Mazza, F. / Aschi, M. / Pochetti, G.
History
DepositionNov 24, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 10, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2023Group: Database references / Category: citation / citation_author / database_2
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 / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Feb 7, 2024Group: 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)69,5603
Polymers69,1662
Non-polymers3941
Water2,720151
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1880 Å2
ΔGint-1 kcal/mol
Surface area26050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.090, 61.480, 118.690
Angle α, β, γ (deg.)90.00, 102.85, 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: 34582.906 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: PET28A / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P37231
#2: Chemical ChemComp-AXY / (2S)-3-(biphenyl-4-yl)-2-(biphenyl-4-yloxy)propanoic acid


Mass: 394.462 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H22O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2.32 Å3/Da / Density % sol: 47 % / Description: prismatic shape
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.8 M NA CITRATE, 0.15 M TRIS, PH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.072 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 2, 2017
RadiationMonochromator: double crystal Si 111 and Si 220 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 2.1→57.859 Å / Num. obs: 37541 / % possible obs: 98.1 % / Redundancy: 2.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.048 / Net I/σ(I): 7.9
Reflection shellResolution: 2.1→2.16 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.466 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 3095 / CC1/2: 0.227 / % possible all: 98.2

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3D6D

3d6d


Resolution: 2.1→57.859 Å / SU ML: 0.41 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 38.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3022 1912 5.1 %
Rwork0.2358 --
obs0.2391 37520 97.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→57.859 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4111 0 30 151 4292
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084216
X-RAY DIFFRACTIONf_angle_d0.9975676
X-RAY DIFFRACTIONf_dihedral_angle_d3.7473092
X-RAY DIFFRACTIONf_chiral_restr0.048657
X-RAY DIFFRACTIONf_plane_restr0.006717
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.15250.44111360.46562568X-RAY DIFFRACTION98
2.1525-2.21070.42721310.42212503X-RAY DIFFRACTION97
2.2107-2.27580.43421400.39832512X-RAY DIFFRACTION98
2.2758-2.34920.39851370.34122553X-RAY DIFFRACTION98
2.3492-2.43320.36771260.32692550X-RAY DIFFRACTION98
2.4332-2.53060.37311450.29392550X-RAY DIFFRACTION98
2.5306-2.64580.35861270.29392543X-RAY DIFFRACTION98
2.6458-2.78530.33341300.26652517X-RAY DIFFRACTION97
2.7853-2.95980.33061380.25822550X-RAY DIFFRACTION99
2.9598-3.18830.34141480.26422527X-RAY DIFFRACTION98
3.1883-3.50910.30191430.22952557X-RAY DIFFRACTION98
3.5091-4.01680.29571240.19852552X-RAY DIFFRACTION97
4.0168-5.06030.26331580.18312546X-RAY DIFFRACTION97
5.0603-57.88070.23941290.19052580X-RAY DIFFRACTION96

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