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- PDB-8zft: Crystal Structure of Human PPARgamma Ligand Binding Domain in Com... -

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Basic information

Entry
Database: PDB / ID: 8zft
TitleCrystal Structure of Human PPARgamma Ligand Binding Domain in Complex with T0070907 and SR1664
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / Nuclear receptors / TZDs / Drug design / Therapeutic targets
Function / homology
Function and homology information


prostaglandin receptor activity / regulation of cholesterol transporter activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation / negative regulation of cellular response to transforming growth factor beta stimulus / negative regulation of cardiac muscle hypertrophy in response to stress / arachidonic acid binding ...prostaglandin receptor activity / regulation of cholesterol transporter activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation / negative regulation of cellular response to transforming growth factor beta stimulus / negative regulation of cardiac muscle hypertrophy in response to stress / arachidonic acid binding / positive regulation of low-density lipoprotein receptor activity / positive regulation of adiponectin secretion / lipoprotein transport / negative regulation of sequestering of triglyceride / DNA binding domain binding / macrophage derived foam cell differentiation / STAT family protein binding / positive regulation of vascular associated smooth muscle cell apoptotic process / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / 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 / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of macrophage derived foam cell differentiation / negative regulation of blood vessel endothelial cell migration / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / white fat cell differentiation / negative regulation of BMP signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / negative regulation of mitochondrial fission / positive regulation of cholesterol efflux / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / retinoic acid receptor signaling pathway / cell fate commitment / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / cell maturation / negative regulation of signaling receptor activity / epithelial cell differentiation / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / hormone-mediated signaling pathway / negative regulation of angiogenesis / response to nutrient / negative regulation of miRNA transcription / negative regulation of MAP kinase activity / fatty acid metabolic process / Regulation of PTEN gene transcription / transcription coregulator binding / peptide binding / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / placenta development / regulation of circadian rhythm / lipid metabolic process / PPARA activates gene expression / positive regulation of DNA-binding transcription factor activity / DNA-binding transcription repressor activity, RNA polymerase II-specific / regulation of blood pressure / positive regulation of miRNA transcription / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / activation of cysteine-type endopeptidase activity involved in apoptotic process / nuclear receptor activity / rhythmic process / glucose homeostasis / cellular response to hypoxia / double-stranded DNA binding / DNA-binding transcription activator activity, RNA polymerase II-specific / DNA-binding transcription factor binding / sequence-specific DNA binding / nucleic acid binding / cell differentiation / receptor complex / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / intracellular membrane-bounded organelle / innate immune response / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of gene expression
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. ...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-3JX / 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsShang, J. / Kojetin, D.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK124870 United States
CitationJournal: Elife / Year: 2024
Title: Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPAR gamma.
Authors: Shang, J. / Kojetin, D.J.
History
DepositionMay 8, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 7, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)64,5506
Polymers62,8992
Non-polymers1,6514
Water00
1
A: Peroxisome proliferator-activated receptor gamma
hetero molecules

B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5506
Polymers62,8992
Non-polymers1,6514
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_455x-1/2,y+1/2,z1
Buried area1810 Å2
ΔGint-12 kcal/mol
Surface area23940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.880, 62.680, 121.040
Angle α, β, γ (deg.)90.000, 102.460, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 31449.520 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pET46 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P37231
#2: Chemical ChemComp-EEY / 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide


Mass: 277.663 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H8ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-3JX / 4'-[(2,3-dimethyl-5-{[(1S)-1-(4-nitrophenyl)ethyl]carbamoyl}-1H-indol-1-yl)methyl]biphenyl-2-carboxylic acid


Mass: 547.600 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H29N3O5 / 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: 2.76 Å3/Da / Density % sol: 55.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.8M SODIUM CITRATE, 100mM MOPS, pH 7.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 16, 2017
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 3.2→59.095 Å / Num. obs: 11555 / % possible obs: 99.87 % / Redundancy: 2 % / CC1/2: 0.995 / Net I/σ(I): 10.7
Reflection shellResolution: 3.2→3.314 Å / Redundancy: 2 % / Num. unique obs: 1163 / CC1/2: 0.809 / % possible all: 100

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Processing

Software
NameVersionClassification
SCALAdata scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
DIALSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.2→59.095 Å / SU ML: 0.53 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 32.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2799 1155 10.01 %
Rwork0.2015 10386 -
obs0.2094 11541 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 148.96 Å2 / Biso mean: 80.4146 Å2 / Biso min: 36.28 Å2
Refinement stepCycle: final / Resolution: 3.2→59.095 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4015 0 118 0 4133
Biso mean--108.68 --
Num. residues----501
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0114210
X-RAY DIFFRACTIONf_angle_d1.375671
X-RAY DIFFRACTIONf_chiral_restr0.061639
X-RAY DIFFRACTIONf_plane_restr0.007717
X-RAY DIFFRACTIONf_dihedral_angle_d4.4042529
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
3.2-3.34560.40611440.28381301
3.3456-3.5220.35291430.27191280
3.522-3.74260.42371440.2951291
3.7426-4.03160.36521430.2211291
4.0316-4.43710.24551410.18521270
4.4371-5.07890.26651440.17111302
5.0789-6.39770.27591460.20341305
6.3977-59.0950.19921500.15981346

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