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- PDB-8b91: Crystal structure of mutant PPARG (C313A) and NCOR2 with an inver... -

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Basic information

Entry
Database: PDB / ID: 8b91
TitleCrystal structure of mutant PPARG (C313A) and NCOR2 with an inverse agonist (compound SI-1)
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 / Notch binding / 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 / Notch binding / 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 / negative regulation of cellular response to transforming growth factor beta stimulus / negative regulation of cardiac muscle hypertrophy in response to stress / : / arachidonate binding / positive regulation of adiponectin secretion / negative regulation of triglyceride storage / DNA binding domain binding / lipoprotein transport / positive regulation of vascular associated smooth muscle cell apoptotic process / STAT family protein binding / WW domain binding / positive regulation of fatty acid metabolic process / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / response to lipid / negative regulation of SMAD protein signal transduction / LBD domain binding / 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 / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / negative regulation of MAPK cascade / retinoic acid receptor signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / estrous cycle / cell maturation / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / negative regulation of signaling receptor activity / positive regulation of adipose tissue development / hormone-mediated signaling pathway / lactation / Regulation of lipid metabolism by PPARalpha / transcription repressor complex / epithelial cell differentiation / peroxisome proliferator activated receptor signaling pathway / response to nutrient / regulation of cellular response to insulin stimulus / cerebellum development / enzyme activator activity / negative regulation of miRNA transcription / peptide binding / SUMOylation of transcription cofactors / negative regulation of angiogenesis / transcription coregulator binding / Regulation of PTEN gene transcription / fatty acid metabolic process / HDACs deacetylate histones / placenta development / positive regulation of apoptotic signaling pathway / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / negative regulation of transforming growth factor beta receptor signaling pathway / mRNA transcription by RNA polymerase II / PPARA activates gene expression / regulation of circadian rhythm / Cytoprotection by HMOX1 / lipid metabolic process / regulation of blood pressure / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / Nuclear Receptor transcription pathway / NOTCH1 Intracellular Domain Regulates Transcription / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / nuclear matrix / histone deacetylase binding
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-Q4O / Peroxisome proliferator-activated receptor gamma / Nuclear receptor corepressor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.23 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)69,4355
Polymers68,9384
Non-polymers4971
Water3,549197
1
A: Peroxisome proliferator-activated receptor gamma
C: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9663
Polymers34,4692
Non-polymers4971
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1260 Å2
ΔGint-11 kcal/mol
Surface area14100 Å2
MethodPISA
2
B: Peroxisome proliferator-activated receptor gamma
D: Nuclear receptor corepressor 2


Theoretical massNumber of molelcules
Total (without water)34,4692
Polymers34,4692
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1040 Å2
ΔGint-8 kcal/mol
Surface area13190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.355, 86.134, 120.855
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: 31830.928 Da / Num. of mol.: 2 / Mutation: C313A
Source method: isolated from a genetically manipulated source
Details: Mutation inserted: C313A / 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-Q4O / ~{N}3-[4-[bis(fluoranyl)methoxy]-3-fluoranyl-phenyl]-4-chloranyl-6-fluoranyl-~{N}1-[(2-methoxyphenyl)methyl]benzene-1,3-dicarboxamide


Mass: 496.839 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H17ClF4N2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / 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: 2.28 Å3/Da / Density % sol: 46.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 3350 20%, NaAc 0.2 M

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Feb 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.23→49.47 Å / Num. obs: 31319 / % possible obs: 99.6 % / Redundancy: 7.3 % / CC1/2: 0.996 / Rrim(I) all: 0.18 / Net I/σ(I): 11.2
Reflection shellResolution: 2.23→2.3 Å / Redundancy: 6.6 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 2810 / CC1/2: 0.419 / Rrim(I) all: 1.409 / % possible all: 99.3

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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: 2.23→49.47 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.935 / SU B: 6.755 / SU ML: 0.158 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.28 / ESU R Free: 0.2 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2277 1611 5.2 %RANDOM
Rwork0.2017 ---
obs0.2031 29654 99.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 110.65 Å2 / Biso mean: 39.786 Å2 / Biso min: 17.71 Å2
Baniso -1Baniso -2Baniso -3
1-0.22 Å20 Å20 Å2
2--0.11 Å2-0 Å2
3----0.33 Å2
Refinement stepCycle: final / Resolution: 2.23→49.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4181 0 34 197 4412
Biso mean--55.34 37.99 -
Num. residues----525
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0134309
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164301
X-RAY DIFFRACTIONr_angle_refined_deg1.4421.6465799
X-RAY DIFFRACTIONr_angle_other_deg1.2411.5839925
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.425523
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.80923.951205
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.5115838
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9821518
X-RAY DIFFRACTIONr_chiral_restr0.0650.2565
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024738
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02907
LS refinement shellResolution: 2.23→2.288 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.349 117 -
Rwork0.312 2165 -
all-2282 -
obs--99.17 %

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