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- PDB-4fgy: Identification of a unique PPAR ligand with an unexpected binding... -

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Basic information

Entry
Database: PDB / ID: 4fgy
TitleIdentification of a unique PPAR ligand with an unexpected binding mode and antibetic activity
Components
  • Nuclear receptor coactivator 1
  • Peroxisome proliferator-activated receptor gamma
KeywordsTranscription/Transferase/Antibiotic / PPAR LBD / nuclear receptor fold / ligand binding / gene transcription / Transcription-Transferase-Antibiotic complex
Function / homology
Function and homology information


labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / 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 / positive regulation of female receptivity / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly ...labyrinthine layer morphogenesis / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / 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 / positive regulation of female receptivity / 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 / hypothalamus development / male mating behavior / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / 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 / estrous cycle / 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 / cellular response to Thyroglobulin triiodothyronine / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / Synthesis of bile acids and bile salts / 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 / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to retinoic acid / negative regulation of signaling receptor activity / histone acetyltransferase activity / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / cell maturation / histone acetyltransferase / cellular response to hormone stimulus / positive regulation of adipose tissue development / epithelial cell differentiation / peroxisome proliferator activated receptor signaling pathway / positive regulation of neuron differentiation / RORA activates gene expression / lactation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cerebellum development / negative regulation of angiogenesis / response to nutrient / negative regulation of MAP kinase activity / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / fatty acid metabolic process / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / negative regulation of miRNA transcription / response to progesterone / placenta development / Regulation of PTEN gene transcription / negative regulation of smooth muscle cell proliferation / nuclear estrogen receptor binding / transcription coregulator binding / nuclear receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / negative regulation of transforming growth factor beta receptor signaling pathway / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II
Similarity search - Function
Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator ...Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / Nuclear receptor coactivator, interlocking / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / Retinoid X Receptor / Retinoid X 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-0W3 / Peroxisome proliferator-activated receptor gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / molecular replacement / Resolution: 2.84 Å
AuthorsWang, R. / Li, Y.
CitationJournal: Diabetologia / Year: 2013
Title: Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor Gamma (PPAR-gamma) ligand with a unique binding mode and effective glucose-lowering ...Title: Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor Gamma (PPAR-gamma) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes.
Authors: Zheng, W. / Feng, X. / Qiu, L. / Pan, Z. / Wang, R. / Lin, S. / Hou, D. / Jin, L. / Li, Y.
History
DepositionJun 5, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2013Provider: repository / Type: Initial release
Revision 1.1May 2, 2018Group: Data collection / Category: diffrn / Item: _diffrn.ambient_temp
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9913
Polymers32,2822
Non-polymers7091
Water32418
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint-7 kcal/mol
Surface area13410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.360, 86.527, 122.691
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 30833.850 Da / Num. of mol.: 1 / Fragment: LIGAND BINDING DOMAIN, UNP RESIDUES 235-504
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1C3, PPARG / Plasmid: pET24a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P37231
#2: Protein/peptide Nuclear receptor coactivator 1 / / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal ...NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal carcinoma antigen NY-REN-52 / Steroid receptor coactivator 1 / SRC-1


Mass: 1447.750 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 686-696 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-0W3 / (4R,6S,8S,12R,14R,16Z,18R,19R,20S,21S)-19,21-dihydroxy-22-{(2S,2'R,5S,5'S)-5'-[(1R)-1-hydroxyethyl]-2,5'-dimethyloctahydro-2,2'-bifuran-5-yl}-4,6,8,12,14,18,20-heptamethyl-9,11-dioxodocos-16-enoic acid / Ionomycin / Ionomycin


Mass: 709.005 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H72O9 / Comment: antibiotic*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 2.36 Å3/Da / Density % sol: 47.83 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7
Details: 0.2 M sodium acetate, 5% ethylene glycol, 20% PEG 3350, pH 7.0, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 1.5862 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Nov 5, 2011 / Details: mirrors
RadiationMonochromator: Diamond [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5862 Å / Relative weight: 1
ReflectionResolution: 2.55→61.345 Å / Num. all: 10291 / Num. obs: 9605 / % possible obs: 93.33 % / Observed criterion σ(F): 2.1 / Observed criterion σ(I): 2.2
Reflection shellResolution: 2.55→2.59 Å / Redundancy: 7.8 % / % possible all: 72.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
d*TREKdata reduction
RefinementResolution: 2.84→35.36 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.875 / SU B: 20.407 / SU ML: 0.396 / Cross valid method: THROUGHOUT / ESU R Free: 0.493 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.28537 344 4.9 %RANDOM
Rwork0.21851 ---
obs0.22181 6706 93.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 44.898 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å20 Å2
2--0.07 Å20 Å2
3---0.16 Å2
Refinement stepCycle: LAST / Resolution: 2.84→35.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2219 0 50 18 2287
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.022315
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6972.0133122
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9285275
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.77725.196102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.04915446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.9321510
X-RAY DIFFRACTIONr_chiral_restr0.110.2369
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211658
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.84→2.913 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.477 27 -
Rwork0.301 449 -
obs--99.58 %

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