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- PDB-3r8a: X-ray crystal structure of the nuclear hormone receptor PPAR-gamm... -

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Basic information

Entry
Database: PDB / ID: 3r8a
TitleX-ray crystal structure of the nuclear hormone receptor PPAR-gamma in a complex with a compound with dual PPAR gamma agonism and Angiotensin II Type I receptor antagonism activity
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsNUCLEAR PROTEIN / Nuclear Hormone Activator / Angiotensin II Type I Receptor Antagonist / Ligand Bound Structure / Diabetes mellitus / Metabolic Syndrome / Obesity
Function / homology
Function and homology information


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 / 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 ...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 / 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 / response to lipid / LBD domain binding / negative regulation of SMAD protein signal transduction / negative regulation of type II interferon-mediated signaling 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 / 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 / positive regulation of adipose tissue development / hormone-mediated signaling pathway / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / response to nutrient / negative regulation of miRNA transcription / peptide binding / negative regulation of angiogenesis / transcription coregulator binding / Regulation of PTEN gene transcription / positive regulation of apoptotic signaling pathway / fatty acid metabolic process / 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 / PPARA activates gene expression / regulation of circadian rhythm / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / lipid metabolic process / regulation of blood pressure / positive regulation of miRNA transcription / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / nuclear receptor activity / rhythmic process / glucose homeostasis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / double-stranded DNA binding / DNA-binding transcription factor binding / cellular response to hypoxia / sequence-specific DNA binding / nucleic acid binding / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / receptor complex / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / innate immune response / intracellular membrane-bounded organelle / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of gene expression
Similarity search - Function
Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type ...Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / : / Retinoid X Receptor / Retinoid X Receptor / 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
Chem-HIG / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.41 Å
AuthorsOhren, J.F.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-gamma.
Authors: Casimiro-Garcia, A. / Filzen, G.F. / Flynn, D. / Bigge, C.F. / Chen, J. / Davis, J.A. / Dudley, D.A. / Edmunds, J.J. / Esmaeil, N. / Geyer, A. / Heemstra, R.J. / Jalaie, M. / Ohren, J.F. / ...Authors: Casimiro-Garcia, A. / Filzen, G.F. / Flynn, D. / Bigge, C.F. / Chen, J. / Davis, J.A. / Dudley, D.A. / Edmunds, J.J. / Esmaeil, N. / Geyer, A. / Heemstra, R.J. / Jalaie, M. / Ohren, J.F. / Ostroski, R. / Ellis, T. / Schaum, R.P. / Stoner, C.
History
DepositionMar 23, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 14, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,5304
Polymers64,6592
Non-polymers8712
Water1,67593
1
A: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7652
Polymers32,3301
Non-polymers4361
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7652
Polymers32,3301
Non-polymers4361
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.697, 61.831, 118.936
Angle α, β, γ (deg.)90.00, 102.04, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 32329.549 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1C3, PPARG / Production host: Escherichia coli (E. coli) / References: UniProt: P37231
#2: Chemical ChemComp-HIG / 2-ethyl-5,7-dimethyl-3-{(1S)-5-[2-(1H-tetrazol-5-yl)phenyl]-2,3-dihydro-1H-inden-1-yl}-3H-imidazo[4,5-b]pyridine


Mass: 435.524 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H25N7
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 93 / Source method: isolated from a natural source / Formula: H2O

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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: 2.58 Å3/Da / Density % sol: 52.28 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: Apo crystals grown from Citrate/Imidazole, then soaked with 0.5 mM compound 2a, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 16, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.41→37.8 Å / Num. all: 24622 / Num. obs: 24537 / % possible obs: 95.67 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.3 % / Biso Wilson estimate: 66.2 Å2 / Rmerge(I) obs: 0.033 / Net I/σ(I): 24
Reflection shellResolution: 2.41→2.52 Å / % possible all: 95.6

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
REFMAC5refinement
BUSTER2.9.6refinement
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 3IA6

3ia6


Resolution: 2.41→37.8 Å / Cor.coef. Fo:Fc: 0.9352 / Cor.coef. Fo:Fc free: 0.8942 / SU R Cruickshank DPI: 0.397 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2807 1287 5.25 %RANDOM
Rwork0.2302 ---
all0.2327 24622 --
obs0.2327 24537 95.67 %-
Displacement parametersBiso mean: 74.54 Å2
Baniso -1Baniso -2Baniso -3
1-1.5178 Å20 Å2-0.1325 Å2
2--0.295 Å20 Å2
3----1.8128 Å2
Refine analyzeLuzzati coordinate error obs: 0.415 Å
Refinement stepCycle: LAST / Resolution: 2.41→37.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3912 0 66 93 4071
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0094071HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.085487HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1457SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes137HARMONIC2
X-RAY DIFFRACTIONt_gen_planes561HARMONIC5
X-RAY DIFFRACTIONt_it4071HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.18
X-RAY DIFFRACTIONt_other_torsion20.7
X-RAY DIFFRACTIONt_chiral_improper_torsion525SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4696SEMIHARMONIC4
LS refinement shellResolution: 2.41→2.52 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.3138 131 5.12 %
Rwork0.267 2430 -
all0.2695 2561 -
obs-4339 95.67 %

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