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- PDB-3g8i: Aleglitazar, a new, potent, and balanced PPAR alpha/gamma agonist... -

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Basic information

Entry
Database: PDB / ID: 3g8i
TitleAleglitazar, a new, potent, and balanced PPAR alpha/gamma agonist for the treatment of type II diabetes
Components
  • Nuclear receptor coactivator 1
  • Peroxisome proliferator-activated receptor alpha
KeywordsTRANSCRIPTION/TRANSFERASE / NUCLEAR HORMONE RECEPTOR / TRANSCRIPTION FACTOR / DIABETES / Activator / DNA-binding / Metal-binding / Nucleus / Polymorphism / Receptor / Transcription / Transcription regulation / Zinc / Zinc-finger / Acyltransferase / Alternative splicing / Chromosomal rearrangement / Phosphoprotein / Proto-oncogene / Transferase / Ubl conjugation / TRANSCRIPTION-TRANSFERASE COMPLEX
Function / homology
Function and homology information


positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / lipoprotein metabolic process / regulation of fatty acid metabolic process / positive regulation of fatty acid oxidation / cellular response to fructose stimulus / regulation of ketone metabolic process / behavioral response to nicotine ...positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / lipoprotein metabolic process / regulation of fatty acid metabolic process / positive regulation of fatty acid oxidation / cellular response to fructose stimulus / regulation of ketone metabolic process / behavioral response to nicotine / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / negative regulation of hepatocyte apoptotic process / mitogen-activated protein kinase kinase kinase binding / negative regulation of leukocyte cell-cell adhesion / labyrinthine layer morphogenesis / ubiquitin conjugating enzyme binding / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / negative regulation of glycolytic process / positive regulation of female receptivity / negative regulation of sequestering of triglyceride / nuclear steroid receptor activity / DNA-binding transcription activator activity / nitric oxide metabolic process / positive regulation of fatty acid metabolic process / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / NFAT protein binding / positive regulation of ATP biosynthetic process / negative regulation of cholesterol storage / negative regulation of macrophage derived foam cell differentiation / cellular response to Thyroglobulin triiodothyronine / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Synthesis of bile acids and bile salts / negative regulation of cytokine production involved in inflammatory response / epidermis development / estrous cycle / phosphatase binding / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / progesterone receptor signaling pathway / nuclear retinoid X receptor binding / positive regulation of lipid biosynthetic process / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / histone acetyltransferase activity / negative regulation of reactive oxygen species biosynthetic process / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / positive regulation of gluconeogenesis / negative regulation of signaling receptor activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / MDM2/MDM4 family protein binding / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / negative regulation of blood pressure / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cellular response to starvation / regulation of cellular response to insulin stimulus / 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 / hippocampus development / gluconeogenesis / 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 transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / wound healing / SUMOylation of intracellular receptors / Heme signaling / response to insulin / mRNA transcription by RNA polymerase II / regulation of circadian rhythm / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / DNA-binding transcription repressor activity, RNA polymerase II-specific / transcription coactivator binding / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex
Similarity search - Function
Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1 / 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 ...Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1 / 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 alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsBenz, J. / Bernardeau, A. / Binggeli, A. / Blum, D. / Boehringer, M. / Grether, U. / Hilpert, H. / Kuhn, B. / Maerki, H.P. / Meyer, M. ...Benz, J. / Bernardeau, A. / Binggeli, A. / Blum, D. / Boehringer, M. / Grether, U. / Hilpert, H. / Kuhn, B. / Maerki, H.P. / Meyer, M. / Puentener, K. / Raab, S. / Ruf, A. / 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 12, 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 alpha
Z: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6703
Polymers32,2332
Non-polymers4381
Water2,792155
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-10 kcal/mol
Surface area13250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.405, 76.033, 98.495
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 alpha / PPAR-alpha / Nuclear receptor subfamily 1 group C member 1


Mass: 30571.697 Da / Num. of mol.: 1 / Fragment: Ligand bind domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARA, NR1C1, PPAR / Plasmid: PET15B / Production host: Escherichia coli (E. coli) / References: UniProt: Q07869
#2: Protein/peptide Nuclear receptor coactivator 1 / Coactivator peptide SRC-1 / NCoA-1 / Steroid receptor coactivator 1 / SRC-1 / RIP160 / Protein Hin- ...Coactivator peptide SRC-1 / NCoA-1 / Steroid receptor coactivator 1 / SRC-1 / RIP160 / Protein Hin-2 / Renal carcinoma antigen NY-REN-52


Mass: 1660.912 Da / Num. of mol.: 1 / Fragment: motif 5 / 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.: 155 / 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: 2.46 Å3/Da / Density % sol: 50.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5
Details: 20-22% PEG 2000, 0.2M NACL, 5% GLYCEROL, 0.1M TRIS-CL, pH 8.5, VAPOR DIFFUSION, 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: Oct 13, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→20 Å / Num. all: 16293 / Num. obs: 16293 / % possible obs: 97.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.7 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 19.2
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.332 / Mean I/σ(I) obs: 4.2 / Num. unique all: 1522 / % possible all: 92.5

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1K71

1k71
PDB Unreleased entry


Resolution: 2.2→15 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.908 / SU B: 6.21 / SU ML: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.273 / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26149 823 5.1 %RANDOM
Rwork0.19909 ---
obs0.20228 15390 97.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 37.356 Å2
Baniso -1Baniso -2Baniso -3
1-1.53 Å20 Å20 Å2
2---2.7 Å20 Å2
3---1.16 Å2
Refinement stepCycle: LAST / Resolution: 2.2→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2103 0 31 155 2289
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0222176
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6841.9932929
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9935258
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1010.2335
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021589
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2490.31064
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2570.5229
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1880.323
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3350.53
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.21621309
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.53132110
X-RAY DIFFRACTIONr_scbond_it2.662867
X-RAY DIFFRACTIONr_scangle_it3.9693819
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.203→2.259 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.275 55
Rwork0.232 994

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