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- PDB-8b8w: Crystal structure of PPARG and NCOR2 with an inverse agonist (com... -

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Basic information

Entry
Database: PDB / ID: 8b8w
TitleCrystal structure of PPARG and NCOR2 with an inverse agonist (compound 7a)
Components
  • Nuclear receptor corepressor 2
  • Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / nuclear hormone receptor transcription factor
Function / homology
Function and homology information


Loss of MECP2 binding ability to the NCoR/SMRT complex / nuclear glucocorticoid receptor binding / negative regulation of androgen receptor signaling pathway / regulation of ketone metabolic process / prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of triglyceride storage / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly ...Loss of MECP2 binding ability to the NCoR/SMRT complex / nuclear glucocorticoid receptor binding / negative regulation of androgen receptor signaling pathway / regulation of ketone metabolic process / prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of triglyceride storage / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly / Notch binding / negative regulation of connective tissue replacement involved in inflammatory response wound healing / positive regulation of cholesterol transport / negative regulation of signaling receptor activity / 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 / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / response to lipid / LBD domain binding / negative regulation of SMAD protein signal transduction / negative regulation of type II interferon-mediated signaling pathway / Notch-HLH transcription pathway / 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 / Regulation of MECP2 expression and activity / 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 / retinoic acid receptor signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / cell maturation / estrous cycle / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of adipose tissue development / hormone-mediated signaling pathway / lactation / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / transcription repressor complex / epithelial cell differentiation / regulation of cellular response to insulin stimulus / response to nutrient / cerebellum development / negative regulation of miRNA transcription / peptide binding / SUMOylation of transcription cofactors / enzyme activator activity / negative regulation of angiogenesis / transcription coregulator binding / Regulation of PTEN gene transcription / positive regulation of apoptotic signaling pathway / fatty acid metabolic process / HDACs deacetylate histones / 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 / Downregulation of SMAD2/3:SMAD4 transcriptional activity / PPARA activates gene expression / regulation of circadian rhythm / Cytoprotection by HMOX1 / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / lipid metabolic process / regulation of blood pressure / positive regulation of miRNA transcription / NOTCH1 Intracellular Domain Regulates Transcription / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / nuclear matrix / histone deacetylase binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants
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
Chem-Q2X / Peroxisome proliferator-activated receptor gamma / Nuclear receptor corepressor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsFriberg, A. / Orsi, D.L. / Pook, E. / Siegel, S. / Lemke, C.T. / Stellfeld, T. / Puetter, V. / Goldstein, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists.
Authors: Orsi, D.L. / Ferrara, S.J. / Siegel, S. / Friberg, A. / Bouche, L. / Pook, E. / Lienau, P. / Bluck, J.P. / Lemke, C.T. / Akcay, G. / Stellfeld, T. / Meyer, H. / Putter, V. / Holton, S.J. / ...Authors: Orsi, D.L. / Ferrara, S.J. / Siegel, S. / Friberg, A. / Bouche, L. / Pook, E. / Lienau, P. / Bluck, J.P. / Lemke, C.T. / Akcay, G. / Stellfeld, T. / Meyer, H. / Putter, V. / Holton, S.J. / Korr, D. / Jerchel-Furau, I. / Pantelidou, C. / Strathdee, C.A. / Meyerson, M. / Eis, K. / Goldstein, J.T.
History
DepositionOct 5, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
C: Nuclear receptor corepressor 2
D: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,8247
Polymers69,0024
Non-polymers8223
Water6,774376
1
A: Peroxisome proliferator-activated receptor gamma
C: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9584
Polymers34,5012
Non-polymers4572
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1800 Å2
ΔGint-16 kcal/mol
Surface area13850 Å2
MethodPISA
2
B: Peroxisome proliferator-activated receptor gamma
D: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8663
Polymers34,5012
Non-polymers3651
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1130 Å2
ΔGint-8 kcal/mol
Surface area13410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.480, 85.310, 119.170
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 31862.994 Da / Num. of mol.: 2
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 2 / N-CoR2 / CTG repeat protein 26 / SMAP270 / Silencing mediator of retinoic acid and thyroid hormone ...N-CoR2 / CTG repeat protein 26 / SMAP270 / Silencing mediator of retinoic acid and thyroid hormone receptor / SMRT / T3 receptor-associating factor / TRAC / Thyroid- / retinoic-acid-receptor-associated corepressor


Mass: 2638.073 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9Y618
#3: Chemical ChemComp-Q2X / 4-chloranyl-~{N}3-phenyl-~{N}1-(phenylmethyl)benzene-1,3-dicarboxamide


Mass: 364.825 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H17ClN2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 376 / 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: 2.19 Å3/Da / Density % sol: 43.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 4000 24%, NaCl 0.2 M, Hepes 0.1 M (pH 7.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.98 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.85→45.15 Å / Num. obs: 51710 / % possible obs: 98.8 % / Redundancy: 6.3 % / Rsym value: 0.1105 / Net I/σ(I): 14.43
Reflection shellResolution: 1.85→1.96 Å / Mean I/σ(I) obs: 2.16 / Num. unique obs: 8600 / Rsym value: 0.65 / % possible all: 92.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 1.86→42.1 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.91 / SU B: 4.852 / SU ML: 0.142 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.162 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2754 2583 5 %RANDOM
Rwork0.2189 ---
obs0.2217 49070 99.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 112.97 Å2 / Biso mean: 33.07 Å2 / Biso min: 12.21 Å2
Baniso -1Baniso -2Baniso -3
1--0.83 Å20 Å20 Å2
2--2.51 Å2-0 Å2
3----1.68 Å2
Refinement stepCycle: final / Resolution: 1.86→42.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4203 0 56 376 4635
Biso mean--39.11 37.73 -
Num. residues----528
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134334
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164329
X-RAY DIFFRACTIONr_angle_refined_deg1.5191.6385830
X-RAY DIFFRACTIONr_angle_other_deg1.3041.5829984
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7935523
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.1623.865207
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.66115839
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3231518
X-RAY DIFFRACTIONr_chiral_restr0.0780.2568
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024763
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02929
LS refinement shellResolution: 1.86→1.905 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.369 176 -
Rwork0.373 3351 -
obs--93.7 %

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