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- PDB-8huq: X-ray structure of human PPAR alpha ligand binding domain-elafibr... -

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Basic information

Entry
Database: PDB / ID: 8huq
TitleX-ray structure of human PPAR alpha ligand binding domain-elafibranor-SRC1 coactivator peptide co-crystals obtained by soaking
Components
  • 15-meric peptide from Nuclear receptor coactivator 1
  • Peroxisome 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 / labyrinthine layer morphogenesis / positive regulation of transcription from RNA polymerase II promoter by galactose / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / negative regulation of glycolytic process / ubiquitin conjugating enzyme binding / mitogen-activated protein kinase kinase kinase binding / positive regulation of fatty acid metabolic process / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / male mating behavior / DNA-binding transcription activator activity / NFAT protein binding / negative regulation of cholesterol storage / hypothalamus development / positive regulation of ATP biosynthetic process / nuclear steroid receptor activity / cellular response to Thyroglobulin triiodothyronine / negative regulation of macrophage derived foam cell differentiation / Synthesis of bile acids and bile salts / progesterone receptor signaling pathway / epidermis development / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / response to retinoic acid / nuclear retinoid X receptor binding / phosphatase binding / estrous cycle / positive regulation of lipid biosynthetic process / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / histone acetyltransferase activity / cellular response to hormone stimulus / Recycling of bile acids and salts / histone acetyltransferase / intracellular receptor signaling pathway / negative regulation of blood pressure / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / nitric oxide metabolic process / hormone-mediated signaling pathway / estrogen receptor signaling pathway / positive regulation of adipose tissue development / negative regulation of reactive oxygen species biosynthetic process / : / lactation / Regulation of lipid metabolism by PPARalpha / response to nutrient / peroxisome proliferator activated receptor signaling pathway / MDM2/MDM4 family protein binding / regulation of cellular response to insulin stimulus / positive regulation of gluconeogenesis / positive regulation of neuron differentiation / 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 / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to progesterone / cerebellum development / cellular response to starvation / nuclear estrogen receptor binding / nuclear receptor binding / gluconeogenesis / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / SUMOylation of intracellular receptors / negative regulation of transforming growth factor beta receptor signaling pathway / mRNA transcription by RNA polymerase II / 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 / cerebral cortex development / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / RNA polymerase II transcription regulator complex / transcription coactivator binding / male gonad development / nuclear receptor activity
Similarity search - Function
Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain ...Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / : / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / Nuclear receptor coactivators bHLH domain / PAS domain / Nuclear receptor coactivator, interlocking / : / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS 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
Similarity search - Domain/homology
Chem-MUO / Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.65 Å
AuthorsKamata, S. / Ishikawa, R. / Akahane, M. / Honda, A. / 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
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.page_first / _citation.pdbx_database_id_PubMed ..._citation.page_first / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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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: 15-meric peptide from Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1814
Polymers32,7042
Non-polymers4772
Water1,53185
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1390 Å2
ΔGint-10 kcal/mol
Surface area12600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.760, 61.573, 53.351
Angle α, β, γ (deg.)90.000, 106.570, 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: Protein/peptide 15-meric peptide from Nuclear receptor coactivator 1


Mass: 1848.177 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-MUO / 2-[2,6-dimethyl-4-[(~{E})-3-(4-methylsulfanylphenyl)-3-oxidanylidene-prop-1-enyl]phenoxy]-2-methyl-propanoic acid / elafibranor


Mass: 384.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24O4S / Feature type: SUBJECT OF INVESTIGATION
#5: 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: 2.15 Å3/Da / Density % sol: 42.91 %
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-17A / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 12, 2020 / 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: 1.65→42.9 Å / Num. obs: 31932 / % possible obs: 95.5 % / Redundancy: 3.5 % / Biso Wilson estimate: 25.87 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.022 / Rpim(I) all: 0.014 / Rrim(I) all: 0.026 / Net I/σ(I): 17.6 / Num. measured all: 111877 / Scaling rejects: 1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.65-1.683.60.3933.215790.870.240.46195.5
9.04-42.93.40.01140.420210.0070.01494.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.42 Å32.8 Å
Translation5.42 Å32.8 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: 7BQ1

7bq1


Resolution: 1.65→32.799 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.94 / Phase error: 23.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2135 3022 4.92 %
Rwork0.1864 58460 -
obs0.1878 31930 93.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.94 Å2 / Biso mean: 34.4439 Å2 / Biso min: 14.77 Å2
Refinement stepCycle: final / Resolution: 1.65→32.799 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2128 0 64 85 2277
Biso mean--50.08 34.69 -
Num. residues----266
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0132240
X-RAY DIFFRACTIONf_angle_d1.3133021
X-RAY DIFFRACTIONf_chiral_restr0.075342
X-RAY DIFFRACTIONf_plane_restr0.008382
X-RAY DIFFRACTIONf_dihedral_angle_d12.1871362
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.6501-1.67580.35331390.2679265093
1.6758-1.70330.27961290.251271494
1.7033-1.73270.26041220.236273694
1.7327-1.76420.28741640.2295262494
1.7642-1.79810.2521520.2223265294
1.7981-1.83480.23691330.218266694
1.8348-1.87470.29111240.2279268594
1.8747-1.91830.24161270.2281268494
1.9183-1.96630.2361330.2246269994
1.9663-2.01940.30051270.2195265494
2.0194-2.07880.25021610.2026259793
2.0788-2.14590.21441270.1974264692
2.1459-2.22260.21611060.1912257390
2.2226-2.31160.22421320.1889244185
2.3116-2.41680.2071530.1829265196
2.4168-2.54410.21611430.2008273895
2.5441-2.70350.20851380.1962271896
2.7035-2.91210.23511430.1952273996
2.9121-3.20490.22391480.199268095
3.2049-3.66810.16441440.1758264894
3.6681-4.61940.18751460.1472247388
4.6194-32.7990.19991310.1641279297

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