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- PDB-4e4k: Crystal Structure of PPARgamma with the ligand JO21 -

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Basic information

Entry
Database: PDB / ID: 4e4k
TitleCrystal Structure of PPARgamma with the ligand JO21
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / bundle of alpha-helices and a small four-stranded beta-sheet / transcription factor
Function / homology
Function and homology information


prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / beige fat cell differentiation / 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 / beige fat cell differentiation / 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 / DNA binding domain binding / negative regulation of cardiac muscle hypertrophy in response to stress / positive regulation of vascular associated smooth muscle cell apoptotic process / positive regulation of fatty acid metabolic process / positive regulation of lipid metabolic process / STAT family protein binding / WW domain binding / response to lipid / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / LBD domain binding / positive regulation of lipoprotein transport / negative regulation of SMAD protein signal transduction / E-box binding / lipid homeostasis / R-SMAD binding / negative regulation of blood vessel endothelial cell migration / white fat cell differentiation / alpha-actinin binding / negative regulation of vascular associated smooth muscle cell proliferation / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / positive regulation of cholesterol efflux / negative regulation of BMP signaling pathway / monocyte differentiation / cell fate commitment / cellular response to low-density lipoprotein particle stimulus / BMP signaling pathway / long-chain fatty acid transport / negative regulation of mitochondrial fission / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / nuclear retinoid X receptor binding / fat cell differentiation / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / retinoic acid receptor signaling pathway / intracellular receptor signaling pathway / negative regulation of MAPK cascade / peptide binding / cell maturation / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / hormone-mediated signaling pathway / positive regulation of adipose tissue development / regulation of cellular response to insulin stimulus / response to nutrient / negative regulation of miRNA transcription / brown fat cell differentiation / negative regulation of angiogenesis / placenta development / Regulation of PTEN gene transcription / transcription coregulator binding / SUMOylation of intracellular receptors / positive regulation of apoptotic signaling pathway / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / PPARA activates gene expression / fatty acid metabolic process / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / regulation of circadian rhythm / mRNA transcription by RNA polymerase II / positive regulation of miRNA transcription / DNA-binding transcription repressor activity, RNA polymerase II-specific / nuclear receptor activity / negative regulation of inflammatory response / regulation of blood pressure / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / 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 / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / signaling 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 / chromatin binding / positive regulation of gene expression
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-RRG / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsPochetti, G. / Montanari, R. / Loiodice, F. / Fracchiolla, G. / Laghezza, A. / Carbonara, G. / Piemontese, L. / Lavecchia, A. / Novellino, E.
Citation
Journal: J.Med.Chem. / Year: 2013
Title: New 2-(Aryloxy)-3-phenylpropanoic Acids as Peroxisome Proliferator-Activated Receptor alpha/gamma Dual Agonists Able To Upregulate Mitochondrial Carnitine Shuttle System Gene Expression.
Authors: Laghezza, A. / Pochetti, G. / Lavecchia, A. / Fracchiolla, G. / Faliti, S. / Piemontese, L. / Di Giovanni, C. / Iacobazzi, V. / Infantino, V. / Montanari, R. / Capelli, D. / Tortorella, P. / Loiodice, F.
#1: Journal: J.Med.Chem. / Year: 2008
Title: Crystal structure of the peroxisome proliferator-activated receptor gamma 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.
#2: Journal: J.Biol.Chem. / Year: 2008
Title: T2384, a novel antidiabetic agent with unique peroxisome proliferator-activated receptor gamma binding properties
Authors: Li, Y. / Wang, Z. / Furukawa, N. / Escaron, P. / Weiszmann, J. / Lee, G. / Lindstrom, M. / Liu, J. / Liu, X. / Xu, H. / Plotnikova, O. / Prasad, V. / Walker, N. / Learned, R.M. / Chen, J.L.
History
DepositionMar 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,1094
Polymers65,3882
Non-polymers7212
Water2,414134
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Peroxisome proliferator-activated receptor gamma
hetero molecules

B: Peroxisome proliferator-activated receptor gamma


Theoretical massNumber of molelcules
Total (without water)66,1094
Polymers65,3882
Non-polymers7212
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_455x-1/2,y+1/2,z1
Buried area2080 Å2
ΔGint-11 kcal/mol
Surface area25570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.010, 62.120, 118.980
Angle α, β, γ (deg.)90.00, 102.42, 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: 32693.824 Da / Num. of mol.: 2 / Fragment: Ligand binding domain (UNP residues 223-505)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P37231
#2: Chemical ChemComp-RRG / (2S)-3-phenyl-2-{[2'-(propan-2-yl)biphenyl-4-yl]oxy}propanoic acid


Mass: 360.446 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H24O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 134 / 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: 2.57 Å3/Da / Density % sol: 52.08 %
Crystal growTemperature: 293 K / pH: 8
Details: 0.8M NACITRATE, 0.15M TRIS, PH8.0, VAPOR DIFFUSION, SITTING DROP, temperature 293 KK

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: May 6, 2010
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 2.5→45 Å / Num. obs: 23188 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Biso Wilson estimate: 53.16 Å2 / Rmerge(I) obs: 0.065 / Net I/σ(I): 12.4
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.449 / Mean I/σ(I) obs: 3 / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
CNSrefinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→10 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: THE ELECTRON DENSITY IN THE REGION OF THE LIGANDS RRG 501 AND RRG 502 WAS WEAK. IT IS POSSIBLE THAT THE LIGANDS ARE DISORDERED. THE DETAILS OF LIGAND MODELING ARE DESCRIBED IN THE MANUSCRIPT.
RfactorNum. reflectionSelection details
Rfree0.335 1095 RANDOM
Rwork0.265 --
obs0.265 22770 -
all-22920 -
Refinement stepCycle: LAST / Resolution: 2.5→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4298 0 54 134 4486
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.31
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it

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