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- PDB-3et1: Structure of PPARalpha with 3-[5-Methoxy-1-(4-methoxy-benzenesulf... -

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Basic information

Entry
Database: PDB / ID: 3et1
TitleStructure of PPARalpha with 3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid
Components
  • Peroxisome proliferator-activated receptor alpha
  • Steroid receptor coactivator 1
KeywordsTranscription/Transferase / PPAR / PPARa / PPARalpha / Drug Discovery / Diabetes / adiponectin / metabolic disease / fragment-based drug discovery / scaffold-based drug discovery / 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 / positive regulation of fatty acid beta-oxidation / regulation of ketone metabolic process / cellular response to fructose stimulus / regulation of fatty acid metabolic process / negative regulation of cell growth involved in cardiac muscle cell development / negative regulation of appetite / negative regulation of hepatocyte apoptotic process ...positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / positive regulation of fatty acid beta-oxidation / regulation of ketone metabolic process / cellular response to fructose stimulus / regulation of fatty acid metabolic process / negative regulation of cell growth involved in cardiac muscle cell development / negative regulation of appetite / negative regulation of hepatocyte apoptotic process / lipoprotein metabolic process / positive regulation of fatty acid oxidation / behavioral response to nicotine / negative regulation of leukocyte cell-cell adhesion / labyrinthine layer morphogenesis / positive regulation of transcription from RNA polymerase II promoter by galactose / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / negative regulation of glycolytic process / ubiquitin conjugating enzyme binding / mitogen-activated protein kinase kinase kinase binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of fatty acid metabolic process / DNA-binding transcription activator activity / male mating behavior / NFAT protein binding / hypothalamus development / negative regulation of cholesterol storage / positive regulation of ATP biosynthetic process / nuclear steroid receptor activity / cellular response to Thyroglobulin triiodothyronine / Synthesis of bile acids and bile salts / negative regulation of macrophage derived foam cell differentiation / progesterone receptor signaling pathway / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / epidermis development / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / response to retinoic acid / phosphatase binding / estrous cycle / nuclear retinoid X receptor binding / positive regulation of lipid biosynthetic process / histone acetyltransferase activity / cellular response to hormone stimulus / Recycling of bile acids and salts / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / histone acetyltransferase / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / negative regulation of blood pressure / intracellular receptor signaling pathway / nitric oxide metabolic process / estrogen receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / hormone-mediated signaling pathway / lactation / : / positive regulation of adipose tissue development / Regulation of lipid metabolism by PPARalpha / MDM2/MDM4 family protein binding / peroxisome proliferator activated receptor signaling pathway / response to nutrient / positive regulation of neuron differentiation / positive regulation of gluconeogenesis / negative regulation of cytokine production involved in inflammatory response / regulation of cellular response to insulin stimulus / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to progesterone / negative regulation of miRNA transcription / cerebellum development / cellular response to starvation / nuclear estrogen receptor binding / nuclear receptor binding / gluconeogenesis / RNA polymerase II transcription regulatory region sequence-specific DNA binding / hippocampus development / SUMOylation of intracellular receptors / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / wound healing / Heme signaling / fatty acid metabolic process / negative regulation of transforming growth factor beta receptor signaling pathway / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / response to insulin / regulation of circadian rhythm / cerebral cortex development / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / RNA polymerase II transcription regulator complex / transcription coactivator binding / male gonad development / nuclear receptor activity
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 / Nuclear receptor coactivators bHLH domain / 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 / 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-ET1 / Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsZhang, K.Y.J. / Wang, W.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2009
Title: Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent
Authors: Artis, D.R. / Lin, J.J. / Zhang, C. / Wang, W. / Mehra, U. / Perreault, M. / Erbe, D. / Krupka, H.I. / England, B.P. / Arnold, J. / Plotnikov, A.N. / Marimuthu, A. / Nguyen, H. / Will, S. / ...Authors: Artis, D.R. / Lin, J.J. / Zhang, C. / Wang, W. / Mehra, U. / Perreault, M. / Erbe, D. / Krupka, H.I. / England, B.P. / Arnold, J. / Plotnikov, A.N. / Marimuthu, A. / Nguyen, H. / Will, S. / Signaevsky, M. / Kral, J. / Cantwell, J. / Settachatgull, C. / Yan, D.S. / Fong, D. / Oh, A. / Shi, S. / Womack, P. / Powell, B. / Habets, G. / West, B.L. / Zhang, K.Y. / Milburn, M.V. / Vlasuk, G.P. / Hirth, K.P. / Nolop, K. / Bollag, G. / Ibrahim, P.N. / Tobin, J.F.
History
DepositionOct 6, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 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

Downloads & links

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Assembly

Deposited unit
A: Peroxisome proliferator-activated receptor alpha
B: Peroxisome proliferator-activated receptor alpha
P: Steroid receptor coactivator 1
Q: Steroid receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,4586
Polymers69,6794
Non-polymers7792
Water1,67593
1
A: Peroxisome proliferator-activated receptor alpha
P: Steroid receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2293
Polymers34,8402
Non-polymers3891
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1390 Å2
ΔGint-10 kcal/mol
Surface area13850 Å2
MethodPISA
2
B: Peroxisome proliferator-activated receptor alpha
Q: Steroid receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2293
Polymers34,8402
Non-polymers3891
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1350 Å2
ΔGint-9 kcal/mol
Surface area13970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.869, 89.595, 101.115
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: 32874.246 Da / Num. of mol.: 2 / Fragment: LIGAND BINDING DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARA, NR1C1, PPAR / Plasmid: pET-28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)RIL / References: UniProt: Q07869
#2: Protein/peptide Steroid receptor coactivator 1 / NCoA-1 / Nuclear receptor coactivator 1 / SRC-1 / RIP160 / Protein Hin-2 / Renal carcinoma antigen NY-REN-52


Mass: 1965.281 Da / Num. of mol.: 2 / Fragment: residues 681-696
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOA1, SRC1 / Plasmid: pET-28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)RIL / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-ET1 / 3-{5-methoxy-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-3-yl}propanoic acid


Mass: 389.422 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19NO6S
#4: 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: 2.73 Å3/Da / Density % sol: 54.88 %
Crystal growTemperature: 277 K / pH: 8
Details: The purified PPARa LBD protein was diluted to 10 mg/ml and 1mM of indeglitazar and 2x molar excess of SRC-1 peptide were added prior to crystallization by mixing equal volumes of ...Details: The purified PPARa LBD protein was diluted to 10 mg/ml and 1mM of indeglitazar and 2x molar excess of SRC-1 peptide were added prior to crystallization by mixing equal volumes of protein/compound sample with reservoir solution containing 16% PEG 8000, 0.1 M Tris buffer at pH 8.0, 0.02 M lithium sulfate, and 5% glycerol, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 14, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 26993 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 4.8 % / Rsym value: 0.045
Reflection shellResolution: 2.5→2.57 Å / Redundancy: 4.9 % / Mean I/σ(I) obs: 1.3 / Rsym value: 0.319 / % possible all: 99.5

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Processing

Software
NameVersionClassification
Blu-Icedata collection
CCP4model building
PHENIX(phenix.refine)refinement
MOSFLMdata reduction
SCALAdata scaling
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1KKQ

1kkq


Resolution: 2.5→44.8 Å / SU ML: 0.41 / σ(F): 1.35 / Phase error: 26.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.258 1352 5.02 %
Rwork0.195 --
obs0.198 26918 99.7 %
all-27007 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 68.83 Å2 / ksol: 0.34 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--15.915 Å2--
2--5.8565 Å2-
3---10.0586 Å2
Refinement stepCycle: LAST / Resolution: 2.5→44.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4499 0 54 93 4646
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d04634
X-RAY DIFFRACTIONf_angle_d0.956251
X-RAY DIFFRACTIONf_dihedral_angle_d17.631757
X-RAY DIFFRACTIONf_chiral_restr0.06712
X-RAY DIFFRACTIONf_plane_restr0794
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.58950.35971220.26272497X-RAY DIFFRACTION99
2.5895-2.69310.29481150.23922556X-RAY DIFFRACTION99
2.6931-2.81570.31421360.21922501X-RAY DIFFRACTION99
2.8157-2.96410.29631520.21542492X-RAY DIFFRACTION100
2.9641-3.14980.31221100.23052559X-RAY DIFFRACTION100
3.1498-3.39290.28161530.2142530X-RAY DIFFRACTION100
3.3929-3.73420.29511330.19492567X-RAY DIFFRACTION100
3.7342-4.27410.20941590.16692548X-RAY DIFFRACTION100
4.2741-5.38350.20651400.15592591X-RAY DIFFRACTION100
5.3835-44.80470.24751320.1832725X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.08940.736-1.09271.70020.03921.9190.1554-0.1770.2665-0.00040.13120.1447-0.2622-0.1234-00.580.0310.10390.40340.04750.45853.340121.197829.6397
22.32420.59541.11252.12080.79461.95070.1096-0.0778-0.0544-0.09980.0328-0.0751-0.0120.15730.00020.3949-0.01240.00780.4994-0.06320.41630.175228.6138-4.7973
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN B

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