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- PDB-6oni: Crystal structure of PPARgamma ligand binding domain in complex w... -

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Basic information

Entry
Database: PDB / ID: 6oni
TitleCrystal structure of PPARgamma ligand binding domain in complex with N-CoR peptide and inverse agonist T0070907
Components
  • NCOR isoform c
  • Peroxisome proliferator-activated receptor gamma
Keywordstranscription/agonist / Nuclear receptors / TZDs / Drug design / Therapeutic targets / TRANSCRIPTION / transcription-agonist complex
Function / homology
Function and homology information


NR1D1 (REV-ERBA) represses gene expression / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of JNK cascade / 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 / negative regulation of glycolytic process / MECP2 regulates transcription factors ...NR1D1 (REV-ERBA) represses gene expression / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of JNK cascade / 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 / negative regulation of glycolytic process / 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 / nuclear thyroid hormone receptor binding / 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 / positive regulation of vascular associated smooth muscle cell apoptotic process / macrophage derived foam cell differentiation / DNA binding domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of SMAD protein signal transduction / negative regulation of fatty acid metabolic process / Notch-HLH transcription pathway / LBD domain binding / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / E-box binding / alpha-actinin binding / negative regulation of blood vessel endothelial cell migration / locomotor rhythm / lipid homeostasis / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / positive regulation of cholesterol efflux / cellular response to low-density lipoprotein particle stimulus / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / histone deacetylase complex / Regulation of MECP2 expression and activity / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / spindle assembly / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / long-chain fatty acid transport / retinoic acid receptor signaling pathway / positive regulation of DNA binding / cell fate commitment / BMP signaling pathway / Nuclear signaling by ERBB4 / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / negative regulation of signaling receptor activity / regulation of cellular response to insulin stimulus / cell maturation / positive regulation of adipose tissue development / epithelial cell differentiation / peroxisome proliferator activated receptor signaling pathway / transcription repressor complex / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / negative regulation of angiogenesis / response to nutrient / negative regulation of MAP kinase activity / fatty acid metabolic process / negative regulation of miRNA transcription / placenta development / Regulation of PTEN gene transcription / negative regulation of smooth muscle cell proliferation / HDACs deacetylate histones / transcription coregulator binding / nuclear receptor binding / Downregulation of SMAD2/3:SMAD4 transcriptional activity / peptide binding / negative regulation of transforming growth factor beta receptor signaling pathway / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / lipid metabolic process / regulation of circadian rhythm / PPARA activates gene expression / Cytoprotection by HMOX1 / mitotic spindle / NOTCH1 Intracellular Domain Regulates Transcription / negative regulation of inflammatory response / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / DNA-binding transcription repressor activity, RNA polymerase II-specific / regulation of blood pressure / Transcriptional regulation of white adipocyte differentiation
Similarity search - Function
N-CoR, GPS2-interacting domain / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / SANT domain / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Myb domain / Myb-like DNA-binding domain / Peroxisome proliferator-activated receptor ...N-CoR, GPS2-interacting domain / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / SANT domain / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Myb domain / Myb-like DNA-binding domain / Peroxisome proliferator-activated receptor / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Retinoid X Receptor / Retinoid X Receptor / Homeobox-like 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
2-chloro-5-nitro-N-(pyridin-4-yl)benzamide / Nuclear receptor corepressor 1 / Peroxisome proliferator-activated receptor gamma / NCOR isoform c
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 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)R01DK101871 United States
CitationJournal: Nat Commun / Year: 2020
Title: A molecular switch regulating transcriptional repression and activation of PPAR gamma.
Authors: Shang, J. / Mosure, S.A. / Zheng, J. / Brust, R. / Bass, J. / Nichols, A. / Solt, L.A. / Griffin, P.R. / Kojetin, D.J.
History
DepositionApr 22, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Peroxisome proliferator-activated receptor gamma
D: NCOR isoform c
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2363
Polymers33,9582
Non-polymers2781
Water7,044391
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1050 Å2
ΔGint-8 kcal/mol
Surface area14130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.876, 61.876, 164.379
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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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.: 1
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) / Strain (production host): BL21(DE3) / References: UniProt: P37231
#2: Protein/peptide NCOR isoform c


Mass: 2508.824 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q86YY1, UniProt: O75376*PLUS
#3: Chemical ChemComp-EEY / 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide


Mass: 277.663 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H8ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 391 / 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: 2.32 Å3/Da / Density % sol: 46.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2M Ammonium sulfate 0.1M MES, pH 6.5 30% w/v, PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 17, 2019
RadiationMonochromator: Liquid nitrogen-cooled double crystal Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.8→34.233 Å / Num. obs: 30550 / % possible obs: 99.49 % / Redundancy: 2 % / Biso Wilson estimate: 25.96 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.01592 / Rpim(I) all: 0.01592 / Rrim(I) all: 0.02251 / Net I/σ(I): 21.08
Reflection shellResolution: 1.8→1.864 Å / Redundancy: 2 % / Rmerge(I) obs: 0.138 / Mean I/σ(I) obs: 3.29 / Num. unique obs: 2995 / CC1/2: 0.956 / Rpim(I) all: 0.138 / Rrim(I) all: 0.1952 / % possible all: 99.93

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
SCALAdata scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6C1I

6c1i


Resolution: 1.8→34.233 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2264 1990 6.55 %
Rwork0.2077 28414 -
obs0.209 30404 99.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 74.11 Å2 / Biso mean: 29.5468 Å2 / Biso min: 9.71 Å2
Refinement stepCycle: final / Resolution: 1.8→34.233 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2193 0 18 391 2602
Biso mean--24.1 30.65 -
Num. residues----274
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072257
X-RAY DIFFRACTIONf_angle_d0.8883040
X-RAY DIFFRACTIONf_chiral_restr0.049351
X-RAY DIFFRACTIONf_plane_restr0.005388
X-RAY DIFFRACTIONf_dihedral_angle_d3.1041920
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.8-1.84510.30471390.27511993100
1.8451-1.89490.32171400.27361983100
1.8949-1.95070.44861330.3439193096
1.9507-2.01360.28111400.24511997100
2.0136-2.08560.31411410.26011991100
2.0856-2.16910.22181400.2152000100
2.1691-2.26780.26791400.2267200099
2.2678-2.38730.23471420.20182032100
2.3873-2.53690.28881390.21242002100
2.5369-2.73270.20641430.20492034100
2.7327-3.00750.211440.21032049100
3.0075-3.44240.2011460.19342072100
3.4424-4.33560.18181460.16852090100
4.3356-34.2330.20141570.19822241100

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