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- PDB-8b92: Crystal structure of PPARG and NCOR2 with an inverse agonist (com... -

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Basic information

Entry
Database: PDB / ID: 8b92
TitleCrystal structure of PPARG and NCOR2 with an inverse agonist (compound SI-2)
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 / negative regulation of androgen receptor signaling pathway / regulation of cellular ketone metabolic process / nuclear glucocorticoid receptor 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 / Notch binding / MECP2 regulates transcription factors ...Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / regulation of cellular ketone metabolic process / nuclear glucocorticoid receptor 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 / Notch binding / 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 / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / DNA binding domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / 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 / lipid homeostasis / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / negative regulation of lipid storage / negative regulation of blood vessel endothelial cell migration / Regulation of MECP2 expression and activity / estrous cycle / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / positive regulation of cholesterol efflux / positive regulation of fat cell differentiation / retinoic acid receptor signaling pathway / negative regulation of osteoblast differentiation / positive regulation of DNA binding / cell fate commitment / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / negative regulation of signaling receptor activity / cell maturation / regulation of cellular response to insulin stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to organonitrogen compound / epithelial cell differentiation / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / transcription repressor complex / lactation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cerebellum development / negative regulation of angiogenesis / response to nutrient / fatty acid metabolic process / SUMOylation of transcription cofactors / negative regulation of miRNA transcription / placenta development / negative regulation of MAP kinase activity / Regulation of PTEN gene transcription / transcription coregulator binding / HDACs deacetylate histones / negative regulation of smooth muscle cell proliferation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / peptide binding / negative regulation of transforming growth factor beta receptor signaling pathway / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / regulation of circadian rhythm / lipid metabolic process / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / nuclear matrix / regulation of blood pressure / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / positive regulation of miRNA transcription / Transcriptional regulation of white adipocyte differentiation / HCMV Early Events / Nuclear Receptor transcription pathway / cellular response to insulin stimulus
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 / 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
Similarity search - Domain/homology
Chem-Q5X / Peroxisome proliferator-activated receptor gamma / Nuclear receptor corepressor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 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

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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)70,0727
Polymers69,0024
Non-polymers1,0703
Water5,999333
1
A: Peroxisome proliferator-activated receptor gamma
C: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0844
Polymers34,5012
Non-polymers5832
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1290 Å2
ΔGint-21 kcal/mol
Surface area13890 Å2
MethodPISA
2
B: Peroxisome proliferator-activated receptor gamma
D: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9883
Polymers34,5012
Non-polymers4871
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-9 kcal/mol
Surface area12850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.257, 85.698, 120.399
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-Q5X / 4-chloranyl-6-fluoranyl-~{N}3-[2-fluoranyl-4-(oxetan-3-yl)phenyl]-~{N}1-[(2-methoxyphenyl)methyl]benzene-1,3-dicarboxamide


Mass: 486.895 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H21ClF2N2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 333 / 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: 2.25 Å3/Da / Density % sol: 45.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 6000 25%, TRIS 0.1 M (pH 8.0), ZnCl 0.01 M

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.66→49.26 Å / Num. obs: 74286 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.999 / Rrim(I) all: 0.092 / Net I/σ(I): 15.12
Reflection shellResolution: 1.66→1.76 Å / Redundancy: 6.7 % / Mean I/σ(I) obs: 1.03 / Num. unique obs: 11836 / CC1/2: 0.353 / Rrim(I) all: 1.965 / % possible all: 99.8

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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: 1.66→49.26 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.951 / SU B: 2.674 / SU ML: 0.084 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.097 / ESU R Free: 0.098 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2274 3715 5 %RANDOM
Rwork0.1953 ---
obs0.1969 70570 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 103.97 Å2 / Biso mean: 29.81 Å2 / Biso min: 14.77 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å20 Å20 Å2
2--0.35 Å2-0 Å2
3----0.21 Å2
Refinement stepCycle: final / Resolution: 1.66→49.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4110 0 71 334 4515
Biso mean--33.86 35.06 -
Num. residues----516
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0134294
X-RAY DIFFRACTIONr_bond_other_d0.0020.0164283
X-RAY DIFFRACTIONr_angle_refined_deg1.8141.665787
X-RAY DIFFRACTIONr_angle_other_deg1.4851.5969880
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6015519
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.48323.831201
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.51315829
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.1881518
X-RAY DIFFRACTIONr_chiral_restr0.0860.2561
X-RAY DIFFRACTIONr_gen_planes_refined0.010.024729
X-RAY DIFFRACTIONr_gen_planes_other0.0090.02929
LS refinement shellResolution: 1.66→1.703 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.369 271 -
Rwork0.342 5150 -
all-5421 -
obs--99.58 %

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