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- PDB-6kxy: Human PPAR alpha ligand binding domain in complex with a syntheti... -

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Basic information

Entry
Database: PDB / ID: 6kxy
TitleHuman PPAR alpha ligand binding domain in complex with a synthetic agonist (compound B)
Components
  • PGC1alpha
  • Peroxisome proliferator-activated receptor 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 / positive regulation of fatty acid oxidation / regulation of fatty acid metabolic process / cellular response to fructose stimulus / regulation of ketone metabolic process / behavioral response to nicotine ...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 / positive regulation of fatty acid oxidation / regulation of fatty acid metabolic process / cellular response to fructose stimulus / regulation of ketone metabolic process / behavioral response to nicotine / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / lipoprotein metabolic process / negative regulation of hepatocyte apoptotic process / mitogen-activated protein kinase kinase kinase binding / negative regulation of leukocyte cell-cell adhesion / ubiquitin conjugating enzyme binding / negative regulation of glycolytic process / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / response to muscle activity / cellular respiration / negative regulation of sequestering of triglyceride / lncRNA binding / nuclear steroid receptor activity / DNA-binding transcription activator activity / nitric oxide metabolic process / temperature homeostasis / positive regulation of fatty acid metabolic process / positive regulation of ATP biosynthetic process / NFAT protein binding / response to starvation / negative regulation of cholesterol storage / intracellular glucose homeostasis / fatty acid oxidation / response to dietary excess / negative regulation of macrophage derived foam cell differentiation / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / negative regulation of cytokine production involved in inflammatory response / epidermis development / phosphatase binding / adipose tissue development / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / brown fat cell differentiation / positive regulation of lipid biosynthetic process / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / negative regulation of reactive oxygen species biosynthetic process / energy homeostasis / negative regulation of signaling receptor activity / digestion / MDM2/MDM4 family protein binding / positive regulation of gluconeogenesis / RORA activates gene expression / negative regulation of blood pressure / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cellular response to starvation / RNA splicing / respiratory electron transport chain / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian gene expression / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / gluconeogenesis / mitochondrion organization / fatty acid metabolic process / nuclear receptor binding / transcription initiation at RNA polymerase II promoter / negative regulation of smooth muscle cell proliferation / positive regulation of DNA-binding transcription factor activity / transcription coregulator activity / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / SUMOylation of intracellular receptors / wound healing / response to insulin / Heme signaling / Transcriptional activation of mitochondrial biogenesis / regulation of circadian rhythm / PPARA activates gene expression / Cytoprotection by HMOX1 / PML body / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / transcription coactivator binding / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / mRNA processing / nuclear receptor activity / Regulation of RUNX2 expression and activity / Circadian Clock / positive regulation of cold-induced thermogenesis / heart development / cellular response to oxidative stress / protein-containing complex assembly / DNA-binding transcription activator activity, RNA polymerase II-specific / DNA-binding transcription factor binding / neuron apoptotic process
Similarity search - Function
PGC-1alpha, RNA recognition motif / PGC-1 / Peroxisome proliferator-activated receptor alpha / Peroxisome proliferator-activated receptor / : / Retinoid X Receptor / Retinoid X Receptor / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. ...PGC-1alpha, RNA recognition motif / PGC-1 / Peroxisome proliferator-activated receptor alpha / 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 / 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 / Nucleotide-binding alpha-beta plait domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-T06 / 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: 2 Å
AuthorsYoshida, T. / Tachibana, K. / Oki, H. / Doi, M. / Fukuda, S. / Yuzuriha, T. / Tabata, R. / Ishimoto, K. / Kawahara, K. / Ohkubo, T. ...Yoshida, T. / Tachibana, K. / Oki, H. / Doi, M. / Fukuda, S. / Yuzuriha, T. / Tabata, R. / Ishimoto, K. / Kawahara, K. / Ohkubo, T. / Miyachi, H. / Doi, T.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science18H03190 Japan
CitationJournal: Sci Rep / Year: 2020
Title: Structural Basis for PPAR alpha Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives.
Authors: Yoshida, T. / Oki, H. / Doi, M. / Fukuda, S. / Yuzuriha, T. / Tabata, R. / Ishimoto, K. / Kawahara, K. / Ohkubo, T. / Miyachi, H. / Doi, T. / Tachibana, K.
History
DepositionSep 14, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 20, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 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 alpha
B: PGC1alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4463
Polymers33,0912
Non-polymers3551
Water1,53185
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1060 Å2
ΔGint-10 kcal/mol
Surface area13110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.548, 61.203, 103.369
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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 (E. coli) / References: UniProt: Q07869
#2: Protein/peptide PGC1alpha


Mass: 2405.782 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UBK2*PLUS
#3: Chemical ChemComp-T06 / 6-ethyl-1-(4-fluorophenyl)-3-pentan-3-yl-pyrazolo[3,4-b]pyridine-4-carboxylic acid


Mass: 355.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22FN3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 85 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 43.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 100 mM HEPES-NaOH, pH 7.4, 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: BL38B1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→45.55 Å / Num. obs: 20224 / % possible obs: 100 % / Redundancy: 12.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.11 / Net I/σ(I): 12.6 / Num. measured all: 250482 / Scaling rejects: 5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Net I/σ(I) obs% possible all
2-2.0512.71.2381852914540.8042.3100
8.94-45.559.50.05626542790.99827.998.7

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
Aimless0.5.32data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1I7G

1i7g


Resolution: 2→41.681 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.01
RfactorNum. reflection% reflection
Rfree0.2571 2024 10.04 %
Rwork0.2093 --
obs0.2142 20160 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 101.22 Å2 / Biso mean: 44.2968 Å2 / Biso min: 18.65 Å2
Refinement stepCycle: final / Resolution: 2→41.681 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2095 0 26 85 2206
Biso mean--43.82 47.07 -
Num. residues----264
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2-2.050.32981170.25421280100
2.05-2.10540.28291500.25291272100
2.1054-2.16740.32921580.24961261100
2.1674-2.23740.27781380.23171256100
2.2374-2.31730.29791440.22961294100
2.3173-2.41010.26221550.22131251100
2.4101-2.51980.27171520.21411289100
2.5198-2.65260.30981390.22621282100
2.6526-2.81870.28261400.23891293100
2.8187-3.03630.29031410.22891310100
3.0363-3.34180.33311630.21561283100
3.3418-3.8250.23491280.19561332100
3.825-4.8180.20431370.17761334100
4.818-41.6810.21721620.2026139999

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