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- PDB-7ahj: Crystal structure of PPARgamma V290M mutant ligand binding domain... -

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Basic information

Entry
Database: PDB / ID: 7ahj
TitleCrystal structure of PPARgamma V290M mutant ligand binding domain in complex with farglitazar
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsNUCLEAR PROTEIN / nuclear receptor
Function / homology
Function and homology information


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 / 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 ...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 / 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 / macrophage derived foam cell differentiation / DNA binding domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / 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 / positive regulation of cholesterol efflux / negative regulation of macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / negative regulation of lipid storage / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / 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 / BMP signaling pathway / nuclear retinoid X receptor binding / negative regulation of signaling receptor activity / regulation of cellular response to insulin stimulus / cell maturation / positive regulation of adipose tissue development / epithelial cell differentiation / peroxisome proliferator activated receptor signaling pathway / hormone-mediated signaling pathway / negative regulation of angiogenesis / response to nutrient / negative regulation of MAP kinase activity / fatty acid metabolic process / negative regulation of miRNA transcription / placenta development / Regulation of PTEN gene transcription / negative regulation of smooth muscle cell proliferation / transcription coregulator binding / peptide binding / negative regulation of transforming growth factor beta receptor signaling pathway / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / lipid metabolic process / regulation of circadian rhythm / PPARA activates gene expression / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / regulation of blood pressure / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / activation of cysteine-type endopeptidase activity involved in apoptotic process / : / rhythmic process / nuclear receptor activity / positive regulation of DNA-binding transcription factor activity / glucose homeostasis / cellular response to hypoxia / double-stranded DNA binding / DNA-binding transcription activator activity, RNA polymerase II-specific / DNA-binding transcription factor binding / sequence-specific DNA binding / nucleic acid binding / cell differentiation / receptor complex / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / innate immune response / intracellular membrane-bounded organelle / negative regulation of DNA-templated transcription / chromatin binding
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 / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors ...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 / 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
Similarity search - Domain/homology
Chem-570 / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsSchoenmakers, E. / Schwabe, B.T.W. / Fairall, L. / Chatterjee, K. / Schwabe, J.W.R.
CitationJournal: To Be Published
Title: Crystal structure of PPARgamma V290M mutant ligand binding domain in complex with farglitazar
Authors: Schoenmakers, E. / Schwabe, B.T.W. / Fairall, L. / Chatterjee, K. / Schwabe, J.W.R.
History
DepositionSep 24, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 14, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)63,3963
Polymers62,8492
Non-polymers5471
Water2,864159
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2900 Å2
ΔGint-20 kcal/mol
Surface area25030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.960, 61.240, 118.510
Angle α, β, γ (deg.)90.000, 103.170, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y

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Components

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


Mass: 31424.535 Da / Num. of mol.: 2 / Mutation: V290M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pET42 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta / References: UniProt: P37231
#2: Chemical ChemComp-570 / 2-(2-BENZOYL-PHENYLAMINO)-3-{4-[2-(5-METHYL-2-PHENYL-OXAZOL-4-YL)-ETHOXY]-PHENYL}-PROPIONIC ACID / GI262570 / Farglitazar / Farglitazar


Mass: 546.612 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H30N2O5 / Comment: agonist*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 159 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.62 Å3/Da / Density % sol: 53.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M TRIS pH8 0.92-1.2M Sodium Citrate 0.1mM TCEP 0.5 micro molar Farglitazar.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Jun 15, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.1→28.94 Å / Num. obs: 38079 / % possible obs: 99.9 % / Redundancy: 3.8 % / Biso Wilson estimate: 29.16 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 10.5
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.329 / Mean I/σ(I) obs: 3.3 / Num. unique obs: 5528 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
PHASER2.1.4phasing
SCALA3.3.16data scaling
MOSFLM7.0.4data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1PRG

1prg


Resolution: 2.1→28.92 Å / SU ML: 0.2464 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.3365
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2366 1902 5 %RANDOM
Rwork0.2002 36153 --
obs0.2021 38055 99.92 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.01 Å2
Refinement stepCycle: LAST / Resolution: 2.1→28.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4104 0 41 159 4304
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00814225
X-RAY DIFFRACTIONf_angle_d1.00115707
X-RAY DIFFRACTIONf_chiral_restr0.042662
X-RAY DIFFRACTIONf_plane_restr0.0066725
X-RAY DIFFRACTIONf_dihedral_angle_d13.6427566
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.150.29571340.24432572X-RAY DIFFRACTION99.89
2.15-2.210.26571380.22312538X-RAY DIFFRACTION99.81
2.21-2.280.27091470.21022547X-RAY DIFFRACTION100
2.28-2.350.22191150.19872589X-RAY DIFFRACTION99.89
2.35-2.430.2761410.20152572X-RAY DIFFRACTION100
2.43-2.530.27131230.20022600X-RAY DIFFRACTION99.96
2.53-2.650.24241260.20282583X-RAY DIFFRACTION99.85
2.65-2.780.26041180.20752596X-RAY DIFFRACTION99.96
2.78-2.960.28771380.22022547X-RAY DIFFRACTION99.93
2.96-3.190.28151400.22182575X-RAY DIFFRACTION100
3.19-3.510.25361320.20622587X-RAY DIFFRACTION100
3.51-4.010.221410.18692609X-RAY DIFFRACTION100
4.01-5.050.17541600.16742593X-RAY DIFFRACTION100
5.05-28.920.22581490.20322645X-RAY DIFFRACTION99.57

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