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- PDB-7e0a: X-ray structure of human PPARgamma ligand binding domain-saroglit... -

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Basic information

Entry
Database: PDB / ID: 7e0a
TitleX-ray structure of human PPARgamma ligand binding domain-saroglitazar co-crystals obtained by co-crystallization
ComponentsIsoform 2 of Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / Nuclear receptor / Protein-ligand complex / PPAR
Function / homology
Function and homology information


negative regulation of pancreatic stellate cell proliferation / response to metformin / RNA polymerase II-specific DNA-binding transcription factor binding => GO:0061629 / DNA-binding transcription factor binding => GO:0140297 / cellular response to vitamin E / cellular response to hyperoxia / negative regulation of miRNA-mediated gene silencing / : / negative regulation of collagen biosynthetic process / response to xenobiotic stimulus => GO:0009410 ...negative regulation of pancreatic stellate cell proliferation / response to metformin / RNA polymerase II-specific DNA-binding transcription factor binding => GO:0061629 / DNA-binding transcription factor binding => GO:0140297 / cellular response to vitamin E / cellular response to hyperoxia / negative regulation of miRNA-mediated gene silencing / : / negative regulation of collagen biosynthetic process / response to xenobiotic stimulus => GO:0009410 / positive regulation of fatty acid oxidation / positive regulation of phagocytosis, engulfment / : / response to vitamin A / prostaglandin receptor activity / regulation of cholesterol transporter activity / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation / response to caffeine / arachidonic acid binding / positive regulation of low-density lipoprotein receptor activity / lipoprotein transport / negative regulation of sequestering of triglyceride / DNA binding domain binding / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / positive regulation of oligodendrocyte differentiation / positive regulation of fatty acid metabolic process / response to lipid / LBD domain binding / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / E-box binding / alpha-actinin binding / lipid homeostasis / response to starvation / fatty acid oxidation / negative regulation of vascular associated smooth muscle cell proliferation / monocyte differentiation / negative regulation of acute inflammatory response / transcription factor binding / negative regulation of macrophage derived foam cell differentiation / negative regulation of blood vessel endothelial cell migration / regulation of lipid metabolic process / cellular response to low-density lipoprotein particle stimulus / negative regulation of BMP signaling pathway / white fat cell differentiation / response to immobilization stress / retinoic acid receptor signaling pathway / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / cell fate commitment / positive regulation of DNA binding / animal organ regeneration / long-chain fatty acid transport / nuclear retinoid X receptor binding / response to mechanical stimulus / cellular response to retinoic acid / cell maturation / negative regulation of signaling receptor activity / epithelial cell differentiation / peroxisome proliferator activated receptor signaling pathway / hormone-mediated signaling pathway / response to cold / negative regulation of angiogenesis / response to nutrient / fatty acid metabolic process / Regulation of PTEN gene transcription / nuclear estrogen receptor binding / transcription initiation at RNA polymerase II promoter / peptide binding / negative regulation of smooth muscle cell proliferation / SUMOylation of intracellular receptors / placenta development / regulation of circadian rhythm / lipid metabolic process / PPARA activates gene expression / negative regulation of cell growth / regulation of blood pressure / positive regulation of DNA-binding transcription factor activity / DNA-binding transcription repressor activity, RNA polymerase II-specific / positive regulation of miRNA transcription / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / response to estrogen / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / cellular response to prostaglandin E stimulus / nuclear receptor activity / activation of cysteine-type endopeptidase activity involved in apoptotic process / : / rhythmic process / glucose homeostasis / heart development / double-stranded DNA binding / protein phosphatase binding / cell differentiation / receptor complex / transcription cis-regulatory region binding
Similarity search - Function
Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / 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 ...Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / 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-EWR / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.771 Å
AuthorsKamata, S. / Honda, A. / Uchii, K. / Machida, Y. / Oyama, T. / Ishii, I.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)16H05107 Japan
Japan Society for the Promotion of Science (JSPS)19K16359 Japan
Japan Agency for Medical Research and Development (AMED)JP19am0101071 Japan
CitationJournal: Biol.Pharm.Bull. / Year: 2021
Title: Structural Basis for Anti-non-alcoholic Fatty Liver Disease and Diabetic Dyslipidemia Drug Saroglitazar as a PPAR alpha / gamma Dual Agonist.
Authors: Honda, A. / Kamata, S. / Satta, C. / Machida, Y. / Uchii, K. / Terasawa, K. / Nemoto, A. / Oyama, T. / Ishii, I.
History
DepositionJan 27, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 22, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2 of Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4182
Polymers31,9781
Non-polymers4401
Water1,56787
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13150 Å2
Unit cell
Length a, b, c (Å)65.798, 65.798, 156.765
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Isoform 2 of Peroxisome proliferator-activated receptor gamma / PPAR-gamma / Nuclear receptor subfamily 1 group C member 3


Mass: 31978.080 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / References: UniProt: P37231-1
#2: Chemical ChemComp-EWR / (2S)-2-ethoxy-3-[4-[2-[2-methyl-5-(4-methylsulfanylphenyl)pyrrol-1-yl]ethoxy]phenyl]propanoic acid


Mass: 439.567 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H29NO4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.61 Å3/Da / Density % sol: 52.84 %
Description: THE ENTRY CONTAINS FRIEDEL PAIRS IN I/F_PLUS/MINUS COLUMNS.
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.1 M Tris (pH 8.5), 1.2 M ammonium sulfate, 0.1 M magnesium chloride hexahydrate

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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: 1.77→46.53 Å / Num. obs: 34460 / % possible obs: 99.9 % / Redundancy: 10.8 % / Biso Wilson estimate: 25.69 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.019 / Rrim(I) all: 0.065 / Net I/σ(I): 23.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.77-1.818.70.3086.218870.9690.1090.32799.1
9.03-46.539.70.0573380.9980.0180.0699

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.11.1-2575-000refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7AWC

7awc


Resolution: 1.771→32.198 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.91 / Phase error: 22.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2205 3176 5 %
Rwork0.1956 60391 -
obs0.1968 34250 99.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 77.15 Å2 / Biso mean: 28.172 Å2 / Biso min: 11.8 Å2
Refinement stepCycle: final / Resolution: 1.771→32.198 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2126 0 59 87 2272
Biso mean--29.52 29.68 -
Num. residues----267
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012273
X-RAY DIFFRACTIONf_angle_d1.0343080
X-RAY DIFFRACTIONf_chiral_restr0.06352
X-RAY DIFFRACTIONf_plane_restr0.006397
X-RAY DIFFRACTIONf_dihedral_angle_d17.661393
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.7713-1.79780.37381410.3038254597
1.7978-1.82590.34781500.263261699
1.8259-1.85580.29011530.253258499
1.8558-1.88780.33811080.2369265198
1.8878-1.92210.26271500.2357255799
1.9221-1.95910.28441370.224265599
1.9591-1.99910.27221160.2201262399
1.9991-2.04250.26631570.2087261099
2.0425-2.090.25671320.2052625100
2.09-2.14230.23141650.20432590100
2.1423-2.20020.25561440.18682657100
2.2002-2.26490.20541260.1962665100
2.2649-2.3380.22281500.19442618100
2.338-2.42150.24881430.20212596100
2.4215-2.51850.19261310.20472642100
2.5185-2.6330.23141420.20712657100
2.633-2.77180.24571200.21372629100
2.7718-2.94530.24151520.21162628100
2.9453-3.17260.27811200.2092659100
3.1726-3.49150.2341330.19092637100
3.4915-3.99590.18141220.17562674100
3.9959-5.03130.15051420.15342635100
5.0313-32.1980.1821420.18412638100

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