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

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Basic information

Entry
Database: PDB / ID: 6kxx
TitleHuman PPAR alpha ligand binding domain in complex with a synthetic agonist (compound A)
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 / positive regulation of fatty acid beta-oxidation / regulation of ketone metabolic process / cellular response to fructose stimulus / regulation of fatty acid metabolic process / negative regulation of cell growth involved in cardiac muscle cell development / negative regulation of appetite ...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 / positive regulation of fatty acid beta-oxidation / regulation of ketone metabolic process / cellular response to fructose stimulus / regulation of fatty acid metabolic process / negative regulation of cell growth involved in cardiac muscle cell development / negative regulation of appetite / negative regulation of hepatocyte apoptotic process / positive regulation of fatty acid oxidation / lipoprotein metabolic process / behavioral response to nicotine / cellular respiration / negative regulation of leukocyte cell-cell adhesion / negative regulation of glycolytic process / ubiquitin conjugating enzyme binding / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / mitogen-activated protein kinase kinase kinase binding / response to starvation / temperature homeostasis / DNA-binding transcription activator activity / positive regulation of fatty acid metabolic process / NFAT protein binding / lncRNA binding / response to muscle activity / negative regulation of cholesterol storage / intracellular glucose homeostasis / fatty acid oxidation / response to dietary excess / positive regulation of ATP biosynthetic process / nuclear steroid receptor activity / 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 / digestion / intracellular receptor signaling pathway / negative regulation of blood pressure / negative regulation of reactive oxygen species biosynthetic process / nitric oxide metabolic process / hormone-mediated signaling pathway / : / Regulation of lipid metabolism by PPARalpha / MDM2/MDM4 family protein binding / response to nutrient / peroxisome proliferator activated receptor signaling pathway / negative regulation of cytokine production involved in inflammatory response / positive regulation of gluconeogenesis / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / RNA splicing / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / cellular response to starvation / nuclear receptor binding / gluconeogenesis / respiratory electron transport chain / transcription coregulator activity / mitochondrion organization / transcription initiation at RNA polymerase II promoter / SUMOylation of intracellular receptors / circadian regulation of gene expression / negative regulation of smooth muscle cell proliferation / wound healing / negative regulation of transforming growth factor beta receptor signaling pathway / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / fatty acid metabolic process / Cytoprotection by HMOX1 / response to insulin / regulation of circadian rhythm / PML body / chromatin DNA binding / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / transcription coactivator binding / 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 / cellular response to oxidative stress / protein-containing complex assembly / DNA-binding transcription activator activity, RNA polymerase II-specific / neuron apoptotic process / response to ethanol / gene expression
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 / 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-T02 / 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: 1.95 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 1.1Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)33,4203
Polymers33,0912
Non-polymers3301
Water2,882160
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 area13280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.060, 60.681, 100.342
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-T02 / 1-(4-chlorophenyl)-6-methyl-3-propan-2-yl-pyrazolo[3,4-b]pyridine-4-carboxylic acid


Mass: 329.781 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16ClN3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 160 / 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: 2.22 Å3/Da / Density % sol: 44.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 100 mM HEPES-NaOH, pH 7.4, 19-23% isopropanol, 19-23% PEG 4000

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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: Dec 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→45.06 Å / Num. obs: 20564 / % possible obs: 99.3 % / Redundancy: 12.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.075 / Net I/σ(I): 19.2 / Num. measured all: 261196 / Scaling rejects: 8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Net I/σ(I) obs% possible all
1.95-213.41.2271903514170.7562.399.3
8.94-45.069.70.04425142580.99857.997.6

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.5.32data scaling
PHENIX1.16_3549refinement
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→29.2955 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 24.42
RfactorNum. reflection% reflection
Rfree0.2362 1999 9.75 %
Rwork0.1879 --
obs0.1925 20511 99.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 106.87 Å2 / Biso mean: 40.9387 Å2 / Biso min: 19.26 Å2
Refinement stepCycle: final / Resolution: 1.95→29.2955 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2163 0 23 160 2346
Biso mean--33.69 44.1 -
Num. residues----274
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.95-1.99880.34011400.2707128899
1.9988-2.05280.32331390.2519129598
2.0528-2.11320.28791380.2271127798
2.1132-2.18140.30951400.2107129398
2.1814-2.25930.26921410.2088131199
2.2593-2.34970.28181400.1945130299
2.3497-2.45660.25461410.1943130099
2.4566-2.58610.25981430.1937131399
2.5861-2.7480.26221430.20991329100
2.748-2.960.23991410.208131599
2.96-3.25750.26681450.20921337100
3.2575-3.7280.251460.17971350100
3.728-4.69380.19691470.15431367100
4.6938-29.29550.18231550.1725143599

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