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- PDB-8yt6: Human PPAR alpha ligand binding domain in complex with a 1H-pyraz... -

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Basic information

Entry
Database: PDB / ID: 8yt6
TitleHuman PPAR alpha ligand binding domain in complex with a 1H-pyrazolo[3,4-b]pyridine-derived compound
Components
  • Peroxisome proliferator-activated receptor alpha
  • Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
KeywordsTRANSCRIPTION / Agonist / Complex / Nuclear receptor
Function / homology
Function and homology information


Regulation of MITF-M dependent genes involved in metabolism / positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / regulation of ketone metabolic process / cellular response to fructose stimulus / regulation of fatty acid metabolic process / negative regulation of appetite / positive regulation of fatty acid beta-oxidation ...Regulation of MITF-M dependent genes involved in metabolism / positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / regulation of ketone metabolic process / cellular response to fructose stimulus / regulation of fatty acid metabolic process / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / lipoprotein metabolic process / positive regulation of fatty acid oxidation / behavioral response to nicotine / cellular respiration / negative regulation of hepatocyte apoptotic process / negative regulation of leukocyte cell-cell adhesion / mitogen-activated protein kinase kinase kinase binding / ubiquitin conjugating enzyme binding / negative regulation of glycolytic process / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / positive regulation of fatty acid metabolic process / DNA-binding transcription activator activity / nuclear steroid receptor activity / temperature homeostasis / positive regulation of ATP biosynthetic process / lncRNA binding / response to muscle activity / NFAT protein binding / negative regulation of cholesterol storage / response to starvation / intracellular glucose homeostasis / fatty acid oxidation / response to dietary excess / negative regulation of macrophage derived foam cell differentiation / epidermis development / adipose tissue development / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / phosphatase binding / brown fat cell differentiation / positive regulation of lipid biosynthetic process / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / energy homeostasis / intracellular receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / digestion / nitric oxide metabolic process / negative regulation of blood pressure / hormone-mediated signaling pathway / : / MDM2/MDM4 family protein binding / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / negative regulation of cytokine production involved in inflammatory response / response to nutrient / positive regulation of gluconeogenesis / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / BMAL1:CLOCK,NPAS2 activates circadian expression / negative regulation of miRNA transcription / RNA splicing / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / positive regulation of DNA-binding transcription factor activity / cellular response to starvation / nuclear receptor binding / respiratory electron transport chain / gluconeogenesis / fatty acid metabolic process / mitochondrion organization / transcription coregulator activity / transcription initiation at RNA polymerase II promoter / response to insulin / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / wound healing / Heme signaling / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / PPARA activates gene expression / regulation of circadian rhythm / Cytoprotection by HMOX1 / PML body / Nuclear Receptor transcription pathway / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / nuclear receptor activity / mRNA processing / Regulation of RUNX2 expression and activity / : / positive regulation of cold-induced thermogenesis / heart development / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to oxidative stress / protein-containing complex assembly / neuron apoptotic process / gene expression
Similarity search - Function
PGC-1alpha, RNA recognition motif / PGC-1 / Peroxisome proliferator-activated receptor alpha / Peroxisome proliferator-activated receptor / : / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily ...PGC-1alpha, RNA recognition motif / PGC-1 / Peroxisome proliferator-activated receptor alpha / Peroxisome proliferator-activated 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
Similarity search - Domain/homology
: / Peroxisome proliferator-activated receptor alpha / Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsTachibana, K. / Morie, T. / Fukuda, S. / Yuzuriha, T. / Ishimoto, K. / Nunomura, K. / Lin, B. / Miyachi, H. / Oki, H. / Kawahara, K. ...Tachibana, K. / Morie, T. / Fukuda, S. / Yuzuriha, T. / Ishimoto, K. / Nunomura, K. / Lin, B. / Miyachi, H. / Oki, H. / Kawahara, K. / Meguro, K. / Nakagawa, S. / Tsujikawa, K. / Akai, S. / Doi, T. / Yoshida, T.
Funding support Japan, 6items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP22ama121054 Japan
Japan Agency for Medical Research and Development (AMED)JP22ama121052 Japan
Japan Society for the Promotion of Science (JSPS)15H02896 Japan
Japan Society for the Promotion of Science (JSPS)16K13044 Japan
Japan Society for the Promotion of Science (JSPS)18H03190 Japan
Japan Society for the Promotion of Science (JSPS)21H03354 Japan
CitationJournal: To Be Published
Title: Structural evolution of 1H-pyrazolo[3,4-b]pyridine-derived PPARalpha activators as leads for nonalcoholic steatohepatitis
Authors: Tachibana, K. / Morie, T. / Fukuda, S. / Yuzuriha, T. / Ishimoto, K. / Nunomura, K. / Lin, B. / Miyachi, H. / Oki, H. / Kawahara, K. / Meguro, K. / Nakagawa, S. / Tsujikawa, K. / Akai, S. / Doi, T. / Yoshida, T.
History
DepositionMar 25, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Peroxisome proliferator-activated receptor alpha
B: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4903
Polymers33,0912
Non-polymers3991
Water1,892105
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1050 Å2
ΔGint-10 kcal/mol
Surface area12490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.647, 61.305, 100.651
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 30684.814 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARA, NR1C1, PPAR / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q07869
#2: Protein/peptide Peroxisome proliferator-activated receptor gamma coactivator 1-alpha / PGC-1-alpha / PPAR-gamma coactivator 1-alpha / PPARGC-1-alpha / Ligand effect modulator 6


Mass: 2405.782 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UBK2
#3: Chemical ChemComp-A1LZX / 6-(2-ethoxyethyl)-1-(4-fluorophenyl)-3-pentan-3-yl-pyrazolo[3,4-b]pyridine-4-carboxylic acid


Mass: 399.459 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26FN3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.13 Å3/Da / Density % sol: 42.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 100 mM HEPES-NaOH, 19-23% PEG 4000, 19-23% 1,2-propanediol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL26B1 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Jul 21, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→45.65 Å / Num. obs: 24883 / % possible obs: 100 % / Redundancy: 13.1 % / Biso Wilson estimate: 36.4 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.023 / Rrim(I) all: 0.085 / Net I/σ(I): 17.4 / Num. measured all: 325262
Reflection shellResolution: 1.85→1.89 Å / % possible obs: 100 % / Redundancy: 13.8 % / Rmerge(I) obs: 1.847 / Num. measured all: 20946 / Num. unique obs: 1521 / CC1/2: 0.653 / Rpim(I) all: 0.511 / Rrim(I) all: 1.918 / Net I/σ(I) obs: 1.6

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→38.9 Å / SU ML: 0.3039 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.6329
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2651 2490 10.03 %
Rwork0.2321 22338 -
obs0.2355 24828 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.32 Å2
Refinement stepCycle: LAST / Resolution: 1.85→38.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2069 0 29 105 2203
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042133
X-RAY DIFFRACTIONf_angle_d0.59132870
X-RAY DIFFRACTIONf_chiral_restr0.0425332
X-RAY DIFFRACTIONf_plane_restr0.0042357
X-RAY DIFFRACTIONf_dihedral_angle_d19.2891799
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.890.42961560.41121197X-RAY DIFFRACTION100
1.89-1.920.33461220.3481244X-RAY DIFFRACTION100
1.92-1.970.36231490.33641205X-RAY DIFFRACTION100
1.97-2.010.36461270.32411238X-RAY DIFFRACTION100
2.01-2.060.37981320.28521220X-RAY DIFFRACTION100
2.06-2.120.29971390.281218X-RAY DIFFRACTION100
2.12-2.180.3161360.29231237X-RAY DIFFRACTION100
2.18-2.250.32861140.2821229X-RAY DIFFRACTION100
2.25-2.330.30981370.27611226X-RAY DIFFRACTION100
2.33-2.420.29061520.25161213X-RAY DIFFRACTION100
2.42-2.530.29431350.24981247X-RAY DIFFRACTION100
2.53-2.670.28961340.26151240X-RAY DIFFRACTION100
2.67-2.830.29831360.25621243X-RAY DIFFRACTION100
2.84-3.050.32181580.26061233X-RAY DIFFRACTION100
3.05-3.360.27951190.23731256X-RAY DIFFRACTION99.93
3.36-3.850.22981360.20721277X-RAY DIFFRACTION100
3.85-4.850.23041490.17681269X-RAY DIFFRACTION100
4.85-38.90.19911590.19821346X-RAY DIFFRACTION99.8

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