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- PDB-9o9n: Crystal structure of PPARgamma ligand binding domain (LBD) in com... -

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Basic information

Entry
Database: PDB / ID: 9o9n
TitleCrystal structure of PPARgamma ligand binding domain (LBD) in complex with NCoR1 corepressor peptide and inverse agonist FX-909
Components
  • Nuclear receptor corepressor 1
  • Peroxisome proliferator-activated receptor gamma
KeywordsNUCLEAR PROTEIN / nuclear / receptor / inverse agonist / cancer / fx-909 / ppar / pparg / ncor / corepressor
Function / homology
Function and homology information


: / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / prostaglandin receptor activity / : / negative regulation of receptor signaling pathway via STAT / negative regulation of glycolytic process / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly ...: / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / prostaglandin receptor activity / : / negative regulation of receptor signaling pathway via STAT / negative regulation of glycolytic process / 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 / nuclear thyroid hormone receptor binding / negative regulation of cellular response to transforming growth factor beta stimulus / arachidonate binding / negative regulation of JNK cascade / positive regulation of adiponectin secretion / DNA binding domain binding / lipoprotein transport / negative regulation of cardiac muscle hypertrophy in response to stress / positive regulation of vascular associated smooth muscle cell apoptotic process / WW domain binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of fatty acid metabolic process / STAT family protein binding / response to lipid / negative regulation of fatty acid metabolic process / negative regulation of SMAD protein signal transduction / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / Notch-HLH transcription pathway / negative regulation of cholesterol storage / lipid homeostasis / E-box binding / locomotor rhythm / alpha-actinin binding / R-SMAD binding / 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 / histone deacetylase complex / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / Regulation of MECP2 expression and activity / positive regulation of cholesterol efflux / negative regulation of BMP signaling pathway / 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 / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Nuclear signaling by ERBB4 / retinoic acid receptor signaling pathway / cell maturation / negative regulation of MAPK cascade / spindle assembly / intracellular receptor signaling pathway / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / hormone-mediated signaling pathway / positive regulation of adipose tissue development / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / transcription repressor complex / response to nutrient / peptide binding / negative regulation of miRNA transcription / placenta development / negative regulation of angiogenesis / transcription coregulator binding / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Regulation of PTEN gene transcription / positive regulation of apoptotic signaling pathway / nuclear receptor binding / HDACs deacetylate histones / negative regulation of smooth muscle cell proliferation / SUMOylation of intracellular receptors / negative regulation of transforming growth factor beta receptor signaling pathway / mRNA transcription by RNA polymerase II / NOTCH1 Intracellular Domain Regulates Transcription / fatty acid metabolic process / Heme signaling / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / regulation of circadian rhythm / Cytoprotection by HMOX1 / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / regulation of blood pressure / lipid metabolic process / positive regulation of miRNA transcription / negative regulation of inflammatory response
Similarity search - Function
N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / SANT domain profile. / Myb domain / SANT domain / Myb-like DNA-binding domain ...N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / SANT domain profile. / 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 / : / Nuclear hormone receptor / Homeobox-like domain superfamily / 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
: / Nuclear receptor corepressor 1 / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsLaughlin, Z.T. / Dong, J. / Harp, J.M. / 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: To Be Published
Title: Structural basis of PPARgamma-mediated transcriptional repression by the covalent inverse agonist FX-909
Authors: Laughlin, Z.T. / Arifova, L. / Munoz-Tello, P. / Yu, X. / Dong, J. / Harp, J.M. / Kojetin, D.J.
History
DepositionApr 18, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2025Provider: repository / Type: Initial release

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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)34,3763
Polymers34,0152
Non-polymers3601
Water73941
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1700 Å2
ΔGint-7 kcal/mol
Surface area14040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.043, 62.043, 166.259
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#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 / PPAR-gamma / Nuclear receptor subfamily 1 group C member 3


Mass: 31506.574 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Production host: Escherichia coli (E. coli) / References: UniProt: P37231
#2: Protein/peptide Nuclear receptor corepressor 1 / N-CoR / N-CoR1


Mass: 2508.824 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: O75376
#3: Chemical ChemComp-A1CAA / (3P)-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile


Mass: 360.335 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H10F2N2O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 2.35 Å3/Da / Density % sol: 47.7 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.1 M MES (pH 6.5), 0.2 M Ammonium Sulfate, 30% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: LIQUID ANODE / Type: Excillum MetalJet D2+ 160 kV / Wavelength: 1.342 Å
DetectorType: Bruker PHOTON III / Detector: PIXEL / Date: Jun 26, 2024
RadiationMonochromator: Helios confocal multilayer / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.342 Å / Relative weight: 1
ReflectionResolution: 2.1→20.89 Å / Num. obs: 18172 / % possible obs: 77.54 % / Redundancy: 7.1 % / Biso Wilson estimate: 18.42 Å2 / Rmerge(I) obs: 0.291 / Net I/σ(I): 4.68
Reflection shellResolution: 2.1→2.175 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.9047 / Mean I/σ(I) obs: 1.03 / Num. unique obs: 1212 / CC1/2: 0.407 / CC star: 0.761 / % possible all: 63.2

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Processing

Software
NameVersionClassification
PROTEUM PLUSBruker Proteum5data collection
PROTEUM PLUSBruker Proteum5data reduction
PROTEUM PLUSBruker Proteum5data scaling
PHASERphasing
PHENIX1.20.1_4487refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→20.89 Å / SU ML: 0.2652 / Cross valid method: FREE R-VALUE / σ(F): 0.02 / Phase error: 28.4553
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2975 1539 10.02 %
Rwork0.2391 13818 -
obs0.2449 15357 77.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.96 Å2
Refinement stepCycle: LAST / Resolution: 2.1→20.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2188 0 21 41 2250
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00822245
X-RAY DIFFRACTIONf_angle_d1.03913027
X-RAY DIFFRACTIONf_chiral_restr0.0515350
X-RAY DIFFRACTIONf_plane_restr0.0074382
X-RAY DIFFRACTIONf_dihedral_angle_d5.0719291
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.170.31861090.2627999X-RAY DIFFRACTION63.13
2.17-2.250.36271070.2918936X-RAY DIFFRACTION59.57
2.25-2.330.32361210.2907984X-RAY DIFFRACTION63.29
2.33-2.440.34361140.29571049X-RAY DIFFRACTION65.52
2.44-2.570.38491290.29561166X-RAY DIFFRACTION73
2.57-2.730.35121370.31261228X-RAY DIFFRACTION77.12
2.73-2.940.36071380.30371218X-RAY DIFFRACTION76.31
2.94-3.240.31541540.281403X-RAY DIFFRACTION86.74
3.24-3.70.28291800.21321621X-RAY DIFFRACTION99.45
3.7-4.650.27041610.17951543X-RAY DIFFRACTION92.41
4.65-20.890.21321890.19081671X-RAY DIFFRACTION94.37
Refinement TLS params.Method: refined / Origin x: 1.33505007055 Å / Origin y: 11.1406521401 Å / Origin z: 14.0047472743 Å
111213212223313233
T0.076117181726 Å20.0442682241922 Å20.0230668895818 Å2-0.134065619806 Å2-0.0453636943044 Å2--0.105509429235 Å2
L0.8591862255 °20.629375241563 °2-0.0450987424932 °2-2.14450694266 °2-1.13288118009 °2--1.22451655786 °2
S-0.0139545784916 Å °-0.0695706237842 Å °-0.0288559974254 Å °-0.00821990388659 Å °0.0583480769994 Å °0.136539388822 Å °0.0430851821329 Å °-0.17000832715 Å °-0.0116195225316 Å °
Refinement TLS groupSelection details: all

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