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- PDB-3g9e: Aleglitaar. a new. potent, and balanced dual ppara/g agonist for ... -

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Basic information

Entry
Database: PDB / ID: 3g9e
TitleAleglitaar. a new. potent, and balanced dual ppara/g agonist for the treatment of type II diabetes
Components
  • Nuclear receptor coactivator 1
  • Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION/TRANSFERASE / NUCLEAR RECEPTOR / TRANSCRIPTION FACTOR / DIABETES / Activator / Alternative splicing / Diabetes mellitus / Disease mutation / DNA-binding / Metal-binding / Nucleus / Obesity / Phosphoprotein / Polymorphism / Receptor / Transcription / Transcription regulation / Zinc / Zinc-finger / Acyltransferase / Chromosomal rearrangement / Proto-oncogene / Transferase / Ubl conjugation / TRANSCRIPTION-TRANSFERASE COMPLEX
Function / homology
Function and homology information


labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / positive regulation of female receptivity / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation ...labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / positive regulation of female receptivity / 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 / 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 / WW domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / hypothalamus development / male mating behavior / response to lipid / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of SMAD protein signal transduction / 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 blood vessel endothelial cell migration / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / cellular response to Thyroglobulin triiodothyronine / white fat cell differentiation / negative regulation of BMP signaling pathway / Synthesis of bile acids and bile salts / cell fate commitment / positive regulation of cholesterol efflux / negative regulation of mitochondrial fission / estrous cycle / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / negative regulation of MAPK cascade / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / BMP signaling pathway / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / retinoic acid receptor signaling pathway / progesterone receptor signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / histone acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / cell maturation / cellular response to hormone stimulus / epithelial cell differentiation / negative regulation of signaling receptor activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / negative regulation of angiogenesis / cerebellum development / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian gene expression / negative regulation of miRNA transcription / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / Regulation of PTEN gene transcription / hippocampus development / transcription coregulator binding / response to progesterone / fatty acid metabolic process / nuclear receptor binding / nuclear estrogen receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / negative regulation of smooth muscle cell proliferation / positive regulation of apoptotic signaling pathway / negative regulation of transforming growth factor beta receptor signaling pathway / peptide binding
Similarity search - Function
Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator ...Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / : / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / PAS 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-RO7 / Peroxisome proliferator-activated receptor gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsRuf, A. / Benz, J. / Bernardeau, A. / Binggeli, A. / Blum, D. / Boehringer, M. / Grether, U. / Hilpert, H. / Kuhn, B. / Maerki, H.P. ...Ruf, A. / Benz, J. / Bernardeau, A. / Binggeli, A. / Blum, D. / Boehringer, M. / Grether, U. / Hilpert, H. / Kuhn, B. / Maerki, H.P. / Meyer, M. / Puenterner, K. / Raab, S. / Schlatter, D. / Gsell, B. / Stihle, M. / Mohr, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Aleglitazar, a new, potent, and balanced dual PPARalpha/gamma agonist for the treatment of type II diabetes.
Authors: Benardeau, A. / Benz, J. / Binggeli, A. / Blum, D. / Boehringer, M. / Grether, U. / Hilpert, H. / Kuhn, B. / Marki, H.P. / Meyer, M. / Puntener, K. / Raab, S. / Ruf, A. / Schlatter, D. / Mohr, P.
History
DepositionFeb 13, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 2, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

Downloads & links

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Assembly

Deposited unit
A: Peroxisome proliferator-activated receptor gamma
B: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9063
Polymers32,4692
Non-polymers4381
Water1,54986
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1040 Å2
ΔGint-8 kcal/mol
Surface area13330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.911, 70.039, 88.478
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 30997.021 Da / Num. of mol.: 1 / Fragment: LIGAND BINDING DOMAIN
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 coactivator 1 / NCoA-1 / Steroid receptor coactivator 1 / SRC-1 / RIP160 / Protein Hin-2 / Renal carcinoma antigen NY-REN-52


Mass: 1471.697 Da / Num. of mol.: 1 / Fragment: CO-ACTIVATOR MOTIF 3 / Source method: obtained synthetically
Details: THE PEPTIDE WAS CHEMICALLY SYNTHESIZED. THE SEQUENCE OF THE PEPTIDE IS NATURALLY FOUND IN HOMO SAPIENS (HUMAN)
References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-RO7 / (2S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1-benzothiophen-7-yl}propanoic acid


Mass: 437.508 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23NO5S / Comment: agonist*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 2.57 Å3/Da / Density % sol: 52.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.2M NaK TARTRATE, 25% PEG 3350, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: OTHER / Wavelength: 1.5418 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Jul 2, 2001 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→20 Å / Num. all: 15017 / Num. obs: 15017 / % possible obs: 98.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 26.3 Å2 / Rsym value: 0.096 / Net I/σ(I): 13.9
Reflection shellResolution: 2.3→2.37 Å / Rmerge(I) obs: 0.309 / Mean I/σ(I) obs: 4.99 / Num. unique all: 1255 / % possible all: 99.8

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Processing

Software
NameVersionClassification
AMoREphasing
CNX2000refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1PRG

1prg


Resolution: 2.3→19.9 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1096794.09 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.262 1455 10 %RANDOM
Rwork0.2 ---
obs-14484 93.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 35.7034 Å2 / ksol: 0.343323 e/Å3
Displacement parametersBiso mean: 34.4 Å2
Baniso -1Baniso -2Baniso -3
1--0.32 Å20 Å20 Å2
2--1.4 Å20 Å2
3----1.07 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.35 Å0.25 Å
Luzzati d res low-5 Å
Luzzati sigma a0.27 Å0.14 Å
Refinement stepCycle: LAST / Resolution: 2.3→19.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2149 0 31 86 2266
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.013
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.5
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.95
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it2.851.5
X-RAY DIFFRACTIONc_mcangle_it3.782
X-RAY DIFFRACTIONc_scbond_it4.652
X-RAY DIFFRACTIONc_scangle_it5.842.5
LS refinement shellResolution: 2.3→2.44 Å / Rfactor Rfree error: 0.018 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.293 261 10.4 %
Rwork0.215 2254 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ro728804.paramro728804.top
X-RAY DIFFRACTION4ion.paramion.top

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