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- PDB-8hhp: Crystal structure of PPARg-LBD complexed with three partial agoni... -

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Basic information

Entry
Database: PDB / ID: 8hhp
TitleCrystal structure of PPARg-LBD complexed with three partial agonists, one nTZDpa and two LT175
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / PPARg-LBD / Partial agonists / nTZDpa / LT175
Function / homology
Function and homology information


prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly / negative regulation of connective tissue replacement involved in inflammatory response wound healing / positive regulation of cholesterol transport / negative regulation of cellular response to transforming growth factor beta stimulus / : / arachidonate binding ...prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly / negative regulation of connective tissue replacement involved in inflammatory response wound healing / positive regulation of cholesterol transport / negative regulation of cellular response to transforming growth factor beta stimulus / : / arachidonate binding / positive regulation of adiponectin secretion / negative regulation of cardiac muscle hypertrophy in response to stress / DNA binding domain binding / lipoprotein transport / positive regulation of vascular associated smooth muscle cell apoptotic process / WW domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / negative regulation of cholesterol storage / lipid homeostasis / E-box binding / alpha-actinin binding / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of blood vessel endothelial cell migration / white fat cell differentiation / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / negative regulation of BMP signaling pathway / positive regulation of cholesterol efflux / negative regulation of mitochondrial fission / cell fate commitment / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / negative regulation of MAPK cascade / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / retinoic acid receptor signaling pathway / cell maturation / intracellular receptor signaling pathway / positive regulation of adipose tissue development / hormone-mediated signaling pathway / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / response to nutrient / negative regulation of miRNA transcription / peptide binding / negative regulation of angiogenesis / transcription coregulator binding / positive regulation of apoptotic signaling pathway / Regulation of PTEN gene transcription / fatty acid metabolic process / placenta development / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / mRNA transcription by RNA polymerase II / PPARA activates gene expression / regulation of circadian rhythm / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / regulation of blood pressure / lipid metabolic process / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / nuclear receptor activity / rhythmic process / glucose homeostasis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / double-stranded DNA binding / DNA-binding transcription factor binding / cellular response to hypoxia / sequence-specific DNA binding / nucleic acid binding / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / receptor complex / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / innate immune response / negative regulation of gene expression / negative regulation of DNA-templated transcription / intracellular membrane-bounded organelle / chromatin binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II
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 / Double treble clef zinc finger, C4 type / Nuclear hormone receptors DNA-binding domain profile. ...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 / 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
(2S)-2-(biphenyl-4-yloxy)-3-phenylpropanoic acid / Chem-NZA / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsKojima, H. / Itoh, T.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED) Japan
CitationJournal: J.Med.Chem. / Year: 2023
Title: Covalent Modifier Discovery Using Hydrogen/Deuterium Exchange-Mass Spectrometry.
Authors: Kojima, H. / Yanagi, R. / Higuchi, E. / Yoshizawa, M. / Shimodaira, T. / Kumagai, M. / Kyoya, T. / Sekine, M. / Egawa, D. / Ohashi, N. / Ishida, H. / Yamamoto, K. / Itoh, T.
History
DepositionNov 16, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)32,5154
Polymers31,4501
Non-polymers1,0653
Water59433
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area830 Å2
ΔGint-20 kcal/mol
Surface area13510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.500, 60.500, 162.260
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Space group name HallP4nw2abw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+3/4
#3: y+1/2,-x+1/2,z+1/4
#4: x+1/2,-y+1/2,-z+1/4
#5: -x+1/2,y+1/2,-z+3/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

#1: Protein Peroxisome proliferator-activated receptor gamma


Mass: 31449.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG / Production host: Escherichia coli (E. coli) / References: UniProt: P37231
#2: Chemical ChemComp-NZA / 5-CHLORO-1-(4-CHLOROBENZYL)-3-(PHENYLTHIO)-1H-INDOLE-2-CARBOXYLIC ACID / NTZDPA


Mass: 428.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H15Cl2NO2S
#3: Chemical ChemComp-LRG / (2S)-2-(biphenyl-4-yloxy)-3-phenylpropanoic acid


Mass: 318.366 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / 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: 2.36 Å3/Da / Density % sol: 47.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.7 / Details: 0.1 M Tris-HCl pH 7.7, 0.75 M sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: May 11, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.45→48.5 Å / Num. obs: 11599 / % possible obs: 99.2 % / Redundancy: 6.4 % / Biso Wilson estimate: 28.63 Å2 / CC1/2: 0.998 / Net I/σ(I): 18
Reflection shellResolution: 2.45→2.57 Å / Num. unique obs: 11599 / CC1/2: 0.948

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2VV3

2vv3


Resolution: 2.45→48.5 Å / SU ML: 0.3383 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 27.9868
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2864 1158 9.99 %
Rwork0.2137 10428 -
obs0.2211 11586 98.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.76 Å2
Refinement stepCycle: LAST / Resolution: 2.45→48.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2088 0 76 33 2197
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00882219
X-RAY DIFFRACTIONf_angle_d1.25362999
X-RAY DIFFRACTIONf_chiral_restr0.067340
X-RAY DIFFRACTIONf_plane_restr0.0062381
X-RAY DIFFRACTIONf_dihedral_angle_d17.3813297
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.45-2.560.33031400.23021267X-RAY DIFFRACTION99.22
2.56-2.70.33411420.24531277X-RAY DIFFRACTION99.37
2.7-2.860.31711410.24241278X-RAY DIFFRACTION99.09
2.87-3.090.36351440.24591287X-RAY DIFFRACTION99.03
3.09-3.40.33661440.23371300X-RAY DIFFRACTION98.9
3.4-3.890.26091450.20861299X-RAY DIFFRACTION98.7
3.89-4.90.24281450.16681316X-RAY DIFFRACTION98.12
4.9-48.50.23891570.20941404X-RAY DIFFRACTION96.54

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