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- PDB-8dkv: PPARg bound to JTP-426467 and Co-R peptide -

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Basic information

Entry
Database: PDB / ID: 8dkv
TitlePPARg bound to JTP-426467 and Co-R peptide
Components
  • Nuclear receptor corepressor 1
  • Peroxisome proliferator-activated receptor gamma
KeywordsNUCLEAR PROTEIN / PPARg / inverse agonist / covalent / JTP-426467
Function / homology
Function and homology information


NR1D1 (REV-ERBA) represses gene expression / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of JNK cascade / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of glycolytic process / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly ...NR1D1 (REV-ERBA) represses gene expression / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of JNK cascade / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of glycolytic process / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation / positive regulation of cholesterol transport / negative regulation of cardiac muscle hypertrophy in response to stress / nuclear thyroid hormone receptor binding / negative regulation of cellular response to transforming growth factor beta stimulus / positive regulation of low-density lipoprotein receptor activity / arachidonate binding / positive regulation of adiponectin secretion / lipoprotein transport / negative regulation of sequestering of triglyceride / DNA binding domain binding / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / negative regulation of fatty acid metabolic process / WW domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of SMAD protein signal transduction / LBD domain binding / Notch-HLH transcription pathway / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / E-box binding / alpha-actinin binding / locomotor rhythm / lipid homeostasis / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / histone deacetylase complex / negative regulation of blood vessel endothelial cell migration / 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 / white fat cell differentiation / negative regulation of BMP signaling pathway / cell fate commitment / positive regulation of cholesterol efflux / negative regulation of mitochondrial fission / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / negative regulation of MAPK cascade / spindle assembly / BMP signaling pathway / retinoic acid receptor 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 / cell maturation / epithelial cell differentiation / negative regulation of signaling receptor activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / transcription repressor complex / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / negative regulation of angiogenesis / response to nutrient / negative regulation of miRNA transcription / Regulation of PTEN gene transcription / transcription coregulator binding / fatty acid metabolic process / nuclear receptor binding / HDACs deacetylate histones / negative regulation of smooth muscle cell proliferation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / positive regulation of apoptotic signaling pathway / negative regulation of transforming growth factor beta receptor signaling pathway / peptide binding / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / regulation of circadian rhythm / Transcriptional activation of mitochondrial biogenesis / placenta development / PPARA activates gene expression / lipid metabolic process / Cytoprotection by HMOX1 / mitotic spindle / NOTCH1 Intracellular Domain Regulates Transcription / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / positive regulation of miRNA transcription / histone deacetylase binding
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 ...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-SKL / Nuclear receptor corepressor 1 / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.59 Å
AuthorsLarsen, N.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Biol.Chem. / Year: 2022
Title: Biochemical and structural basis for the pharmacological inhibition of nuclear hormone receptor PPAR gamma by inverse agonists.
Authors: Irwin, S. / Karr, C. / Furman, C. / Tsai, J. / Gee, P. / Banka, D. / Wibowo, A.S. / Dementiev, A.A. / O'Shea, M. / Yang, J. / Lowe, J. / Mitchell, L. / Ruppel, S. / Fekkes, P. / Zhu, P. / ...Authors: Irwin, S. / Karr, C. / Furman, C. / Tsai, J. / Gee, P. / Banka, D. / Wibowo, A.S. / Dementiev, A.A. / O'Shea, M. / Yang, J. / Lowe, J. / Mitchell, L. / Ruppel, S. / Fekkes, P. / Zhu, P. / Korpal, M. / Larsen, N.A.
History
DepositionJul 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 7, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 25, 2023Group: 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
C: Nuclear receptor corepressor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6736
Polymers32,7262
Non-polymers9474
Water3,927218
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1350 Å2
ΔGint-19 kcal/mol
Surface area15480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.160, 81.630, 48.010
Angle α, β, γ (deg.)90.000, 104.060, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-807-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AC

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


Mass: 31151.186 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: 1574.885 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: O75376

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Non-polymers , 4 types, 222 molecules

#3: Chemical ChemComp-SKL / 2-chloro-N-[4-(5-methyl-1,3-benzoxazol-2-yl)phenyl]-5-nitrobenzamide


Mass: 407.807 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H14ClN3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CXS / 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID


Mass: 221.317 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H19NO3S / Comment: pH buffer*YM
#5: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 218 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.42 Å3/Da / Density % sol: 49.07 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop
Details: 2+2 uL drops made from a 2:2:1 molar ratio of JTP-4:NCOR peptide:PPARg and well solution containing 1.8-2.2 M (NH3)2SO4, 0.2 M Li2SO4 and 100 mM CAPS pH 9.5. Protein formulated at 20 mg mL-1 ...Details: 2+2 uL drops made from a 2:2:1 molar ratio of JTP-4:NCOR peptide:PPARg and well solution containing 1.8-2.2 M (NH3)2SO4, 0.2 M Li2SO4 and 100 mM CAPS pH 9.5. Protein formulated at 20 mg mL-1 in 20 mM Tris, pH 8.0, 100 mM NaCl, and 1mM TCEP

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Data collection

DiffractionMean temperature: 120 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 13, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.59→46.57 Å / Num. obs: 38701 / % possible obs: 92.8 % / Redundancy: 2.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.027 / Rrim(I) all: 0.046 / Net I/σ(I): 14.1 / Num. measured all: 106204
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.59-1.632.50.453673326490.7870.3310.5642.185.8
7.11-46.572.60.02512504790.9980.0170.0329.497.5

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Processing

Software
NameVersionClassification
Aimless0.5.25data scaling
REFMAC5.8.0103refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PRG

2prg


Resolution: 1.59→46.57 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.934 / SU B: 3.071 / SU ML: 0.106 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.11 / ESU R Free: 0.115 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.266 1955 5.1 %RANDOM
Rwork0.216 ---
obs0.2185 36745 92.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 145.77 Å2 / Biso mean: 36.763 Å2 / Biso min: 15.2 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å20.01 Å2
2---0.01 Å20 Å2
3---0.01 Å2
Refinement stepCycle: final / Resolution: 1.59→46.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2219 0 61 222 2502
Biso mean--35.9 42.46 -
Num. residues----279
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.022323
X-RAY DIFFRACTIONr_bond_other_d0.0050.022311
X-RAY DIFFRACTIONr_angle_refined_deg2.0492.0173131
X-RAY DIFFRACTIONr_angle_other_deg1.3473.0095335
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7135278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.64425.40898
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.70315437
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.623159
X-RAY DIFFRACTIONr_chiral_restr0.1270.2362
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022523
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02488
LS refinement shellResolution: 1.59→1.631 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 133 -
Rwork0.315 2512 -
all-2645 -
obs--85.54 %

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