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- PDB-8hun: X-ray structure of human PPAR alpha ligand binding domain-seladel... -

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Basic information

Entry
Database: PDB / ID: 8hun
TitleX-ray structure of human PPAR alpha ligand binding domain-seladelpar co-crystals obtained by cross-seeding
ComponentsPeroxisome proliferator-activated receptor alpha
KeywordsTRANSCRIPTION / Nuclear receptor / Protein-ligand complex / PPAR
Function / homology
Function and homology information


positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / positive regulation of fatty acid beta-oxidation / cellular response to fructose stimulus / regulation of ketone metabolic process / 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 transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / positive regulation of fatty acid beta-oxidation / cellular response to fructose stimulus / regulation of ketone metabolic process / 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 / lipoprotein metabolic process / positive regulation of fatty acid oxidation / behavioral response to nicotine / negative regulation of leukocyte cell-cell adhesion / negative regulation of glycolytic process / ubiquitin conjugating enzyme binding / mitogen-activated protein kinase kinase kinase binding / positive regulation of fatty acid metabolic process / DNA-binding transcription activator activity / NFAT protein binding / negative regulation of cholesterol storage / positive regulation of ATP biosynthetic process / nuclear steroid receptor activity / negative regulation of macrophage derived foam cell differentiation / epidermis development / phosphatase binding / positive regulation of lipid biosynthetic process / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / intracellular receptor signaling pathway / negative regulation of blood pressure / nitric oxide metabolic process / hormone-mediated signaling pathway / negative regulation of reactive oxygen species biosynthetic process / : / Regulation of lipid metabolism by PPARalpha / response to nutrient / peroxisome proliferator activated receptor signaling pathway / MDM2/MDM4 family protein binding / positive regulation of gluconeogenesis / negative regulation of cytokine production involved in inflammatory response / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / BMAL1:CLOCK,NPAS2 activates circadian expression / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / cellular response to starvation / gluconeogenesis / SUMOylation of intracellular receptors / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / fatty acid metabolic process / wound healing / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / regulation of circadian rhythm / response to insulin / Cytoprotection by HMOX1 / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / transcription coactivator binding / nuclear receptor activity / : / heart development / DNA-binding transcription activator activity, RNA polymerase II-specific / response to ethanol / gene expression / sequence-specific DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / response to hypoxia / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / lipid binding / chromatin / positive regulation of DNA-templated transcription / protein-containing complex binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Peroxisome proliferator-activated receptor alpha / Peroxisome proliferator-activated receptor / : / 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 ...Peroxisome proliferator-activated receptor alpha / Peroxisome proliferator-activated receptor / : / 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
Similarity search - Domain/homology
Seladelpar / Peroxisome proliferator-activated receptor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.01 Å
AuthorsKamata, S. / Honda, A. / Machida, Y. / Uchii, K. / Shiiyama, Y. / Masuda, R. / Iino, S. / Oyama, T. / Ishii, I.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)22K15049 Japan
Japan Society for the Promotion of Science (JSPS)22H05577 Japan
Japan Agency for Medical Research and Development (AMED)JP21am0101071 Japan
CitationJournal: Antioxidants / Year: 2023
Title: Functional and Structural Insights into the Human PPAR alpha / delta / gamma Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor.
Authors: Kamata, S. / Honda, A. / Ishikawa, R. / Akahane, M. / Fujita, A. / Kaneko, C. / Miyawaki, S. / Habu, Y. / Shiiyama, Y. / Uchii, K. / Machida, Y. / Oyama, T. / Ishii, I.
History
DepositionDec 24, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 9, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2023Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author / struct
Item: _citation.page_first / _citation.pdbx_database_id_PubMed ..._citation.page_first / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _struct.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Peroxisome proliferator-activated receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,3933
Polymers30,8561
Non-polymers5372
Water1,24369
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.567, 61.512, 53.177
Angle α, β, γ (deg.)90.000, 106.290, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Peroxisome proliferator-activated receptor alpha


Mass: 30856.053 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pet28a / Production host: Escherichia coli (E. coli) / References: UniProt: Q07869
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-KKB / Seladelpar


Mass: 444.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23F3O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / 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: 2.27 Å3/Da / Density % sol: 45.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 0.1 M Tris (pH 8.5), 25%(w/v) PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-5A / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 20, 2022 / Details: Mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.01→42.78 Å / Num. obs: 18470 / % possible obs: 99.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 20.82 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.05 / Rrim(I) all: 0.093 / Net I/σ(I): 11.3 / Num. measured all: 63156
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.3 %

Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.01-2.060.3543.113600.8680.2290.42399.8
8.99-42.780.02436.62170.9990.0150.02998.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.49 Å42.78 Å
Translation5.49 Å42.78 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.5.21data scaling
PHASER2.7.16phasing
PHENIX1.11.1-2575-000refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6KAX

6kax


Resolution: 2.01→42.778 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.92 / Phase error: 22.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2283 1737 4.94 %
Rwork0.2001 33405 -
obs0.2014 18454 97.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 64.22 Å2 / Biso mean: 23.6713 Å2 / Biso min: 11.31 Å2
Refinement stepCycle: final / Resolution: 2.01→42.778 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2064 0 66 69 2199
Biso mean--31.25 21.87 -
Num. residues----260
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032232
X-RAY DIFFRACTIONf_angle_d0.5073015
X-RAY DIFFRACTIONf_chiral_restr0.036340
X-RAY DIFFRACTIONf_plane_restr0.002382
X-RAY DIFFRACTIONf_dihedral_angle_d10.5641359
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.01-2.06920.23061680.2458273497
2.0692-2.1360.281450.2362284998
2.136-2.21230.28591440.2246275298
2.2123-2.30090.23771470.2255279597
2.3009-2.40560.28261370.2232271596
2.4056-2.53240.28761790.2314276097
2.5324-2.6910.26891510.2264280798
2.691-2.89880.2771210.2168280798
2.8988-3.19040.27291280.2308279297
3.1904-3.65180.20951370.1942281598
3.6518-4.60010.16651490.1508277397
4.6001-42.7780.15731310.1602280697

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