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- PDB-6pdz: Crystal structure of PPARgamma ligand binding domain in complex w... -

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Basic information

Entry
Database: PDB / ID: 6pdz
TitleCrystal structure of PPARgamma ligand binding domain in complex with SMRT peptide and inverse agonist T0070907
Components
  • Nuclear receptor corepressor 2
  • Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / Nuclear receptors / TZDs / Drug design / Therapeutic targets
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 vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly / Notch binding ...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 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 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 / 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 / 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 / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / retinoic acid receptor signaling pathway / cell maturation / estrous cycle / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / intracellular receptor signaling pathway / positive regulation of adipose tissue development / hormone-mediated signaling pathway / lactation / Regulation of lipid metabolism by PPARalpha / transcription repressor complex / peroxisome proliferator activated receptor signaling pathway / 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 / positive regulation of apoptotic signaling pathway / Regulation of PTEN gene transcription / 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 / Downregulation of SMAD2/3:SMAD4 transcriptional activity / mRNA transcription by RNA polymerase II / PPARA activates gene expression / regulation of circadian rhythm / Cytoprotection by HMOX1 / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / regulation of blood pressure / NOTCH1 Intracellular Domain Regulates Transcription / lipid metabolic process / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / RNA polymerase II transcription regulator complex / nuclear matrix
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 / : / Retinoid X Receptor / Retinoid X Receptor / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
2-chloro-5-nitro-N-(pyridin-4-yl)benzamide / Peroxisome proliferator-activated receptor gamma / Nuclear receptor corepressor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 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)R01DK101871 United States
CitationJournal: Nat Commun / Year: 2020
Title: A molecular switch regulating transcriptional repression and activation of PPAR gamma.
Authors: Shang, J. / Mosure, S.A. / Zheng, J. / Brust, R. / Bass, J. / Nichols, A. / Solt, L.A. / Griffin, P.R. / Kojetin, D.J.
History
DepositionJun 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 9, 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
B: Peroxisome proliferator-activated receptor gamma
C: Nuclear receptor corepressor 2
A: Peroxisome proliferator-activated receptor gamma
D: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6546
Polymers68,0994
Non-polymers5552
Water9,584532
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3830 Å2
ΔGint-17 kcal/mol
Surface area25560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.756, 93.484, 114.607
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: 31449.520 Da / Num. of mol.: 2
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 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: 2599.999 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOR2, CTG26 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q9Y618
#3: Chemical ChemComp-EEY / 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide


Mass: 277.663 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H8ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 532 / 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: 47.67 %
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 PEG8000

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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: Apr 26, 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: 2.1→37.823 Å / Num. obs: 38114 / % possible obs: 99.6 % / Redundancy: 2 % / Biso Wilson estimate: 21.5 Å2 / Rmerge(I) obs: 0.031 / Net I/σ(I): 12.4
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 2 % / Rmerge(I) obs: 0.236 / Mean I/σ(I) obs: 3 / Num. unique obs: 3776 / % possible all: 99.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
SCALAdata scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ONI

6oni


Resolution: 2.1→37.82 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 23.39
RfactorNum. reflection% reflection
Rfree0.241 2000 5.25 %
Rwork0.191 36097 -
obs0.194 38097 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 82.9 Å2 / Biso mean: 26.78 Å2 / Biso min: 9.41 Å2
Refinement stepCycle: final / Resolution: 2.1→37.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4350 0 36 532 4918
Biso mean--24.61 31.74 -
Num. residues----543
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.1-2.15250.29811420.2296255399
2.1525-2.21070.28541400.222545100
2.2107-2.27580.28581410.21392543100
2.2758-2.34920.25211420.20722552100
2.3492-2.43310.28861380.2116250399
2.4331-2.53050.2761440.20022580100
2.5305-2.64570.26641410.19662556100
2.6457-2.78510.26011410.19442549100
2.7851-2.95960.24791430.19252585100
2.9596-3.1880.24411430.20322570100
3.188-3.50860.22681420.1812256899
3.5086-4.01580.19121450.16812611100
4.0158-5.05760.19391460.16082642100
5.0576-37.820.24861520.1998274099

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