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- PDB-8fhe: Crystal structure of PPARgamma ligand-binding domain in complex w... -

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Basic information

Entry
Database: PDB / ID: 8fhe
TitleCrystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and GW9662
Components
  • Nuclear receptor corepressor 1
  • Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / Nuclear receptors / TZDs / Drug design / Therapeutic targets / transcription-agonist complex
Function / homology
Function and homology information


: / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of glycolytic process / prostaglandin receptor activity / : / nuclear thyroid hormone receptor binding / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation ...: / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of glycolytic process / prostaglandin receptor activity / : / nuclear thyroid hormone receptor binding / 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 / negative regulation of JNK cascade / 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 / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of vascular associated smooth muscle cell apoptotic process / negative regulation of fatty acid metabolic process / WW domain binding / positive regulation of fatty acid metabolic process / STAT family protein binding / response to lipid / Notch-HLH transcription pathway / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / negative regulation of cholesterol storage / locomotor rhythm / negative regulation of SMAD protein signal transduction / E-box binding / lipid homeostasis / alpha-actinin binding / R-SMAD binding / histone deacetylase complex / negative regulation of vascular associated smooth muscle cell proliferation / monocyte differentiation / negative regulation of blood vessel endothelial cell migration / white fat cell differentiation / negative regulation of macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / Regulation of MECP2 expression and activity / negative regulation of lipid storage / negative regulation of BMP signaling pathway / positive regulation of cholesterol efflux / cell fate commitment / negative regulation of osteoblast differentiation / negative regulation of mitochondrial fission / positive regulation of fat cell differentiation / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Nuclear signaling by ERBB4 / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / retinoic acid receptor signaling pathway / cell maturation / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / spindle assembly / negative regulation of MAPK cascade / intracellular receptor signaling pathway / hormone-mediated signaling pathway / positive regulation of adipose tissue development / Regulation of lipid metabolism by PPARalpha / transcription repressor complex / peroxisome proliferator activated receptor signaling pathway / response to nutrient / epithelial cell differentiation / regulation of cellular response to insulin stimulus / peptide binding / negative regulation of miRNA transcription / negative regulation of angiogenesis / placenta development / nuclear receptor binding / positive regulation of apoptotic signaling pathway / Regulation of PTEN gene transcription / transcription coregulator binding / HDACs deacetylate histones / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / mRNA transcription by RNA polymerase II / Heme signaling / fatty acid metabolic process / negative regulation of transforming growth factor beta receptor signaling pathway / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / regulation of circadian rhythm / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / NOTCH1 Intracellular Domain Regulates Transcription / lipid metabolic process / positive regulation of miRNA transcription / regulation of blood pressure / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / Constitutive Signaling by NOTCH1 PEST Domain Mutants
Similarity search - Function
N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Myb domain / SANT domain / Myb-like DNA-binding domain ...N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Myb domain / SANT domain / Myb-like DNA-binding domain / Peroxisome proliferator-activated receptor / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / : / Homeobox-like domain superfamily / 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
2-chloro-5-nitro-N-phenylbenzamide / Nuclear receptor corepressor 1 / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / 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)6R01DK124870 United States
CitationJournal: Nat Commun / Year: 2025
Title: Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.
Authors: MacTavish, B.S. / Zhu, D. / Shang, J. / Shao, Q. / He, Y. / Yang, Z.J. / Kamenecka, T.M. / Kojetin, D.J.
History
DepositionDec 14, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.2Apr 30, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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
B: Peroxisome proliferator-activated receptor gamma
D: Nuclear receptor corepressor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2353
Polymers33,9582
Non-polymers2771
Water4,864270
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1000 Å2
ΔGint-8 kcal/mol
Surface area13820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.721, 61.721, 163.918
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 Nuclear receptor corepressor 1 / N-CoR / N-CoR1


Mass: 2508.824 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOR1, KIAA1047 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: O75376
#3: Chemical ChemComp-GW9 / 2-chloro-5-nitro-N-phenylbenzamide


Mass: 276.675 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H9ClN2O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 270 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.3 Å3/Da / Density % sol: 46.49 %
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: Jun 14, 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→34.14 Å / Num. obs: 30317 / % possible obs: 99.93 % / Redundancy: 2 % / Biso Wilson estimate: 25.91 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.01343 / Rpim(I) all: 0.01343 / Rrim(I) all: 0.01899 / Net I/σ(I): 28
Reflection shellResolution: 1.8→1.864 Å / Redundancy: 2 % / Rmerge(I) obs: 0.1565 / Num. unique obs: 2980 / CC1/2: 0.941 / Rpim(I) all: 0.1565

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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: 1.8→34.14 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 22.3 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2286 2000 6.6 %
Rwork0.1966 --
obs0.1987 30307 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→34.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2182 0 18 270 2470
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062274
X-RAY DIFFRACTIONf_angle_d0.8643062
X-RAY DIFFRACTIONf_dihedral_angle_d3.1191938
X-RAY DIFFRACTIONf_chiral_restr0.049354
X-RAY DIFFRACTIONf_plane_restr0.005390
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.8450.28961400.27221985X-RAY DIFFRACTION100
1.845-1.89490.26331400.22661962X-RAY DIFFRACTION100
1.8949-1.95070.27811390.22041988X-RAY DIFFRACTION100
1.9507-2.01360.27521400.21331965X-RAY DIFFRACTION100
2.0136-2.08560.26781410.2072001X-RAY DIFFRACTION100
2.0856-2.16910.24641400.2041976X-RAY DIFFRACTION100
2.1691-2.26780.25451400.20391998X-RAY DIFFRACTION100
2.2678-2.38730.23751430.20212013X-RAY DIFFRACTION100
2.3873-2.53690.24351410.21062003X-RAY DIFFRACTION100
2.5369-2.73260.24381430.2052027X-RAY DIFFRACTION100
2.7326-3.00750.26421440.21152025X-RAY DIFFRACTION100
3.0075-3.44230.211450.19232063X-RAY DIFFRACTION100
3.4423-4.33560.20571470.16182075X-RAY DIFFRACTION100
4.3356-34.140.18961570.19392226X-RAY DIFFRACTION100

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