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- PDB-5z6s: Crystal structure of the PPARgamma-LBD complexed with compound DS-6930 -

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Basic information

Entry
Database: PDB / ID: 5z6s
TitleCrystal structure of the PPARgamma-LBD complexed with compound DS-6930
Components
  • Peptide from Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
  • Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION
Function / homology
Function and homology information


Regulation of MITF-M dependent genes involved in metabolism / positive regulation of fatty acid oxidation / cellular respiration / 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 ...Regulation of MITF-M dependent genes involved in metabolism / positive regulation of fatty acid oxidation / cellular respiration / 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 / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / 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 / lipoprotein transport / 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 / temperature homeostasis / response to starvation / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / lncRNA binding / negative regulation of cholesterol storage / negative regulation of SMAD protein signal transduction / response to muscle activity / lipid homeostasis / E-box binding / intracellular glucose homeostasis / alpha-actinin binding / response to dietary excess / fatty acid oxidation / R-SMAD binding / energy homeostasis / 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 / adipose tissue development / BMP signaling pathway / long-chain fatty acid transport / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / nuclear retinoid X receptor binding / brown fat cell differentiation / 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 / digestion / hormone-mediated signaling pathway / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / response to nutrient / epithelial cell differentiation / regulation of cellular response to insulin stimulus / positive regulation of gluconeogenesis / peptide binding / RNA splicing / negative regulation of miRNA transcription / SUMOylation of transcription cofactors / negative regulation of angiogenesis / placenta development / Regulation of PTEN gene transcription / positive regulation of apoptotic signaling pathway / nuclear receptor binding / transcription coregulator binding / gluconeogenesis / respiratory electron transport chain / mitochondrion organization / transcription coregulator activity / transcription initiation at RNA polymerase II promoter / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / mRNA transcription by RNA polymerase II / circadian regulation of gene expression / fatty acid metabolic process / chromatin DNA binding / negative regulation of transforming growth factor beta receptor signaling pathway / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / regulation of circadian rhythm / PML body / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway
Similarity search - Function
PGC-1alpha, RNA recognition motif / PGC-1 / 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 / RNA recognition motif ...PGC-1alpha, RNA recognition motif / PGC-1 / 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 / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / 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 / Nucleotide-binding alpha-beta plait domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-RTF / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsMatsui, Y. / Hanzawa, H.
CitationJournal: Bioorg. Med. Chem. / Year: 2018
Title: Discovery of DS-6930, a potent selective PPAR gamma modulator. Part II: Lead optimization.
Authors: Shinozuka, T. / Tsukada, T. / Fujii, K. / Tokumaru, E. / Shimada, K. / Onishi, Y. / Matsui, Y. / Wakimoto, S. / Kuroha, M. / Ogata, T. / Araki, K. / Ohsumi, J. / Sawamura, R. / Watanabe, N. ...Authors: Shinozuka, T. / Tsukada, T. / Fujii, K. / Tokumaru, E. / Shimada, K. / Onishi, Y. / Matsui, Y. / Wakimoto, S. / Kuroha, M. / Ogata, T. / Araki, K. / Ohsumi, J. / Sawamura, R. / Watanabe, N. / Yamamoto, H. / Fujimoto, K. / Tani, Y. / Mori, M. / Tanaka, J.
History
DepositionJan 25, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 17, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 24, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 22, 2023Group: 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
C: Peptide from Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9545
Polymers34,4802
Non-polymers4743
Water4,234235
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1300 Å2
ΔGint-26 kcal/mol
Surface area13180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.657, 54.154, 66.557
Angle α, β, γ (deg.)90.00, 106.82, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 32412.576 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Production host: Escherichia coli (E. coli) / References: UniProt: P37231
#2: Protein/peptide Peptide from Peroxisome proliferator-activated receptor gamma coactivator 1-alpha / PPARGC-1-alpha / Ligand effect modulator 6


Mass: 2067.381 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UBK2
#3: Chemical ChemComp-RTF / 3-[[6-(3,5-dimethylpyridin-2-yl)oxy-1-methyl-benzimidazol-2-yl]methoxy]benzoic acid


Mass: 403.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21N3O4
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.18 Å3/Da / Density % sol: 43.69 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: PEG 4000, sodium thiocyanate, Tris-hydrochloride

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Dec 17, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 26418 / % possible obs: 95.2 % / Redundancy: 6.6 % / Biso Wilson estimate: 20.4 Å2 / Rsym value: 0.04 / Net I/σ(I): 36.3
Reflection shellResolution: 1.8→1.86 Å / Num. unique obs: 2557 / Rsym value: 0.292 / % possible all: 93.2

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Processing

Software
NameVersionClassification
CNS1.2refinement
HKL-2000data reduction
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3V9T

3v9t


Resolution: 1.8→19.77 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 930455.3 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.226 2641 10 %RANDOM
Rwork0.199 ---
obs0.199 26351 95.2 %-
Solvent computationBsol: 46.0745 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso mean: 23.2 Å2
Baniso -1Baniso -2Baniso -3
1-2.41 Å20 Å20.95 Å2
2---0.43 Å20 Å2
3----1.98 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.23 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.15 Å0.08 Å
Refinement stepCycle: 1 / Resolution: 1.8→19.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2154 0 30 235 2419
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
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_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d18.8
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.75
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.261.5
X-RAY DIFFRACTIONc_mcangle_it1.972
X-RAY DIFFRACTIONc_scbond_it1.992
X-RAY DIFFRACTIONc_scangle_it3.072.5
LS refinement shellResolution: 1.8→1.91 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.317 399 9.4 %
Rwork0.285 3864 -
obs--93.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3RTC-3294.paramRTC-3294.top
X-RAY DIFFRACTION4ion.param

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