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- PDB-9t5s: Crystal structure of human PPARalpha in complex with co-activator... -

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Basic information

Entry
Database: PDB / ID: 9t5s
TitleCrystal structure of human PPARalpha in complex with co-activator PGC-1 alpha peptide and bempedoic acid
Components
  • Peroxisome proliferator-activated receptor alpha
  • Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
KeywordsTRANSCRIPTION / Peroxisome proliferator-activated receptor alpha (PPARalpha) / bempedoic acid (BA) / nuclear receptor / activator
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 / negative regulation of cell growth involved in cardiac muscle cell development / regulation of fatty acid metabolic process / 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 / negative regulation of cell growth involved in cardiac muscle cell development / regulation of fatty acid metabolic process / negative regulation of appetite / negative regulation of hepatocyte apoptotic process / positive regulation of fatty acid oxidation / behavioral response to nicotine / lipoprotein metabolic process / cellular respiration / negative regulation of leukocyte cell-cell adhesion / : / negative regulation of glycolytic process / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / ubiquitin conjugating enzyme binding / mitogen-activated protein kinase kinase kinase binding / response to starvation / positive regulation of fatty acid metabolic process / DNA-binding transcription activator activity / NFAT protein binding / response to muscle activity / temperature homeostasis / lncRNA binding / negative regulation of cholesterol storage / fatty acid oxidation / response to dietary excess / intracellular glucose homeostasis / 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 / positive regulation of lipid biosynthetic process / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / energy homeostasis / digestion / : / negative regulation of blood pressure / intracellular receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / nitric oxide metabolic process / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / peroxisome proliferator activated receptor signaling pathway / negative regulation of cytokine production involved in inflammatory response / MDM2/MDM4 family protein binding / response to nutrient / brown fat cell differentiation / BMAL1:CLOCK,NPAS2 activates circadian expression / positive regulation of gluconeogenesis / SUMOylation of transcription cofactors / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Activation of gene expression by SREBF (SREBP) / negative regulation of miRNA transcription / RNA splicing / cellular response to starvation / nuclear receptor binding / gluconeogenesis / respiratory electron transport chain / transcription coregulator activity / mitochondrion organization / SUMOylation of intracellular receptors / transcription initiation at RNA polymerase II promoter / circadian regulation of gene expression / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / wound healing / Heme signaling / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / Cytoprotection by HMOX1 / fatty acid metabolic process / regulation of circadian rhythm / PML body / chromatin DNA binding / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / response to insulin / 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 / protein-containing complex assembly / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to oxidative stress / neuron apoptotic process / gene expression / sequence-specific DNA binding
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: 1.74 Å
AuthorsUseini, A. / Strater, N. / Kuenze, G. / Heiker, J.T. / Sheikh, B.N.
Funding support Germany, 3items
OrganizationGrant numberCountry
German Research Foundation (DFG)457240345 Germany
Helmholtz Association Germany
German Research Foundation (DFG)209933838 Germany
CitationJournal: To Be Published
Title: Bempedoic acid binds and activates PPARalpha independently of ACSVL1
Authors: Useini, A.
History
DepositionNov 5, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 17, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)70,3146
Polymers69,6254
Non-polymers6892
Water6,125340
1
A: Peroxisome proliferator-activated receptor alpha
B: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1573
Polymers34,8132
Non-polymers3441
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1180 Å2
ΔGint-8 kcal/mol
Surface area13530 Å2
MethodPISA
2
C: Peroxisome proliferator-activated receptor alpha
D: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1573
Polymers34,8132
Non-polymers3441
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-10 kcal/mol
Surface area13280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.253, 99.748, 61.612
Angle α, β, γ (deg.)90.00, 99.80, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 32745.135 Da / Num. of mol.: 2
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 Peroxisome proliferator-activated receptor gamma coactivator 1-alpha / PGC-1-alpha / PPAR-gamma coactivator 1-alpha / PPARGC-1-alpha / Ligand effect modulator 6


Mass: 2067.381 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UBK2
#3: Chemical ChemComp-A1JTY / Bempedoic acid / 2,2,14,14-tetramethyl-8-oxidanyl-pentadecanedioic acid


Mass: 344.486 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C19H36O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 340 / 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: 2.62 Å3/Da / Density % sol: 53.06 %
Crystal growTemperature: 292.15 K / Method: vapor diffusion, sitting drop / Details: 20 %w/v PEG 3350, 0.2 M Na2HPO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.97626 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 17, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 1.74→60.71 Å / Num. obs: 58151 / % possible obs: 94.1 % / Redundancy: 7.1 % / CC1/2: 0.99 / Net I/σ(I): 12.9
Reflection shellResolution: 1.74→1.86 Å / Num. unique obs: 2908 / CC1/2: 0.567

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Processing

Software
NameVersionClassification
PHENIX(1.21.2_5419: ???)refinement
PDB_EXTRACTdata extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.74→38.54 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.3 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2113 2988 5.14 %
Rwork0.1781 --
obs0.1798 58141 79.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.74→38.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4461 0 48 340 4849
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064700
X-RAY DIFFRACTIONf_angle_d0.8686354
X-RAY DIFFRACTIONf_dihedral_angle_d13.0231792
X-RAY DIFFRACTIONf_chiral_restr0.04726
X-RAY DIFFRACTIONf_plane_restr0.007810
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.74-1.770.2885130.2525181X-RAY DIFFRACTION
1.77-1.80.3139340.2884548X-RAY DIFFRACTION
1.8-1.830.3292390.2792911X-RAY DIFFRACTION27
1.83-1.870.2819740.26561318X-RAY DIFFRACTION39
1.87-1.90.29611110.2521665X-RAY DIFFRACTION52
1.9-1.950.30971020.25052176X-RAY DIFFRACTION65
1.95-1.990.27761290.23562540X-RAY DIFFRACTION77
1.99-2.040.26611320.22372859X-RAY DIFFRACTION86
2.04-2.10.23281730.21153187X-RAY DIFFRACTION96
2.1-2.160.24161660.20043348X-RAY DIFFRACTION100
2.16-2.230.21841730.18383277X-RAY DIFFRACTION100
2.23-2.310.21761690.17283332X-RAY DIFFRACTION100
2.31-2.40.2331920.16863270X-RAY DIFFRACTION99
2.4-2.510.22181830.17383279X-RAY DIFFRACTION99
2.51-2.640.21821620.18073332X-RAY DIFFRACTION99
2.64-2.810.21681840.19373302X-RAY DIFFRACTION100
2.81-3.020.23142030.17793319X-RAY DIFFRACTION100
3.02-3.330.20681990.18563297X-RAY DIFFRACTION100
3.33-3.810.191640.15743335X-RAY DIFFRACTION100
3.81-4.80.16171770.14123319X-RAY DIFFRACTION99
4.8-38.540.20592090.18213358X-RAY DIFFRACTION99

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