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- PDB-8huk: X-ray structure of human PPAR alpha ligand binding domain-lanifib... -

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Basic information

Entry
Database: PDB / ID: 8huk
TitleX-ray structure of human PPAR alpha ligand binding domain-lanifibranor-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 / regulation of fatty acid metabolic process / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / positive regulation of fatty acid oxidation / regulation of cellular ketone metabolic process / cellular response to fructose stimulus / behavioral response to nicotine / negative regulation of appetite ...positive regulation of transformation of host cell by virus / regulation of fatty acid transport / regulation of fatty acid metabolic process / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / positive regulation of fatty acid oxidation / regulation of cellular ketone metabolic process / cellular response to fructose stimulus / 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 / labyrinthine layer morphogenesis / ubiquitin conjugating enzyme binding / regulation of thyroid hormone mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / negative regulation of glycolytic process / positive regulation of female receptivity / negative regulation of sequestering of triglyceride / nuclear steroid receptor activity / hypothalamus development / DNA-binding transcription activator activity / male mating behavior / positive regulation of fatty acid metabolic process / nitric oxide metabolic process / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of ATP biosynthetic process / NFAT protein binding / negative regulation of cholesterol storage / negative regulation of macrophage derived foam cell differentiation / estrous cycle / cellular response to Thyroglobulin triiodothyronine / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Synthesis of bile acids and bile salts / negative regulation of cytokine production involved in inflammatory response / epidermis development / phosphatase binding / MDM2/MDM4 family protein binding / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / positive regulation of lipid biosynthetic process / response to retinoic acid / negative regulation of signaling receptor activity / histone acetyltransferase activity / negative regulation of reactive oxygen species biosynthetic process / positive regulation of gluconeogenesis / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / negative regulation of blood pressure / RORA activates gene expression / lactation / cellular response to starvation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cerebellum development / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian gene expression / fatty acid metabolic process / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / negative regulation of miRNA transcription / nuclear receptor coactivator activity / response to progesterone / gluconeogenesis / nuclear estrogen receptor binding / nuclear receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / Heme signaling / response to insulin / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / wound healing / Transcriptional activation of mitochondrial biogenesis / regulation of circadian rhythm / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / male gonad development / nuclear receptor activity / Circadian Clock
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 / PAS domain / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Nuclear receptor coactivator, interlocking / 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 / 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
Similarity search - Domain/homology
Chem-BJB / 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: 2.981 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
C: Peroxisome proliferator-activated receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9954
Polymers63,5603
Non-polymers4351
Water0
1
A: Peroxisome proliferator-activated receptor alpha
B: 15-meric peptide from Nuclear receptor coactivator 1


Theoretical massNumber of molelcules
Total (without water)32,7042
Polymers32,7042
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-9 kcal/mol
Surface area13680 Å2
MethodPISA
2
C: Peroxisome proliferator-activated receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,2912
Polymers30,8561
Non-polymers4351
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.733, 101.383, 60.361
Angle α, β, γ (deg.)90.000, 98.480, 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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / 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-BJB / 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]butanoic acid


Mass: 434.916 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15ClN2O4S2 / Feature type: SUBJECT OF INVESTIGATION
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: 2.84 Å3/Da / Density % sol: 56.75 %
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-17A / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 8, 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: 2.98→45.48 Å / Num. obs: 14504 / % possible obs: 99.3 % / Redundancy: 3.4 % / Biso Wilson estimate: 81.21 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.032 / Rrim(I) all: 0.06 / Net I/σ(I): 12.3 / Num. measured all: 49712 / 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
2.98-3.163.10.31534.123370.9490.2110.3898.8
8.94-45.483.30.02535540.9980.0160.0397.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.22 Å39.2 Å
Translation6.22 Å39.2 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: 3SP6

3sp6


Resolution: 2.981→39.202 Å / SU ML: 0.4 / Cross valid method: FREE R-VALUE / σ(F): 1.87 / Phase error: 34.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2537 1501 5.57 %
Rwork0.1974 25451 -
obs0.2005 14434 94.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 181.05 Å2 / Biso mean: 100.2106 Å2 / Biso min: 49.35 Å2
Refinement stepCycle: final / Resolution: 2.981→39.202 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4194 0 42 0 4236
Biso mean--116.87 --
Num. residues----528
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024299
X-RAY DIFFRACTIONf_angle_d0.4055799
X-RAY DIFFRACTIONf_chiral_restr0.033665
X-RAY DIFFRACTIONf_plane_restr0.002735
X-RAY DIFFRACTIONf_dihedral_angle_d11.9072623
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.9812-3.07740.43641500.3347201984
3.0774-3.18730.43161230.2991234594
3.1873-3.31490.33351350.2466232095
3.3149-3.46560.26461660.2247233696
3.4656-3.64820.3051270.2209235296
3.6482-3.87660.22061390.195233596
3.8766-4.17560.27411480.189235696
4.1756-4.59520.30261460.1814238396
4.5952-5.25880.2161260.1787231695
5.2588-6.62040.26051110.2326229592
6.6204-39.2020.17641300.1572239498

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