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- PDB-2rew: Crystal Structure of PPARalpha ligand binding domain with BMS-631707 -

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Basic information

Entry
Database: PDB / ID: 2rew
TitleCrystal Structure of PPARalpha ligand binding domain with BMS-631707
ComponentsPeroxisome proliferator-activated receptor alpha
KeywordsTRANSCRIPTION / alpha helical / Activator / DNA-binding / Metal-binding / Nucleus / Polymorphism / Receptor / Transcription regulation / Zinc / Zinc-finger
Function / homology
Function and homology information


positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / regulation of fatty acid metabolic process / negative regulation of cell growth involved in cardiac muscle cell development / positive regulation of fatty acid oxidation / cellular response to fructose stimulus / regulation of cellular ketone metabolic process / behavioral response to nicotine / negative regulation of appetite ...positive regulation of transformation of host cell by virus / regulation of fatty acid transport / enamel mineralization / regulation of fatty acid metabolic process / negative regulation of cell growth involved in cardiac muscle cell development / positive regulation of fatty acid oxidation / cellular response to fructose stimulus / regulation of cellular ketone metabolic process / behavioral response to nicotine / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / lipoprotein metabolic process / negative regulation of hepatocyte apoptotic process / mitogen-activated protein kinase kinase kinase binding / negative regulation of leukocyte cell-cell adhesion / ubiquitin conjugating enzyme binding / negative regulation of glycolytic process / 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 / positive regulation of ATP biosynthetic process / NFAT protein binding / negative regulation of cholesterol storage / negative regulation of macrophage derived foam cell differentiation / negative regulation of cytokine production involved in inflammatory response / epidermis development / phosphatase binding / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of lipid biosynthetic process / negative regulation of reactive oxygen species biosynthetic process / negative regulation of signaling receptor activity / MDM2/MDM4 family protein binding / positive regulation of gluconeogenesis / RORA activates gene expression / negative regulation of blood pressure / Regulation of lipid metabolism by PPARalpha / cellular response to starvation / hormone-mediated signaling pathway / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian gene expression / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / fatty acid metabolic process / gluconeogenesis / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / wound healing / Heme signaling / SUMOylation of intracellular receptors / response to insulin / Transcriptional activation of mitochondrial biogenesis / regulation of circadian rhythm / PPARA activates gene expression / Cytoprotection by HMOX1 / transcription coactivator binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / nuclear receptor activity / Circadian Clock / heart development / DNA-binding transcription activator activity, RNA polymerase II-specific / DNA-binding transcription factor binding / response to ethanol / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / cell differentiation / response to hypoxia / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / lipid binding / protein-containing complex binding / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Peroxisome proliferator-activated receptor alpha / 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 / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors ...Peroxisome proliferator-activated receptor alpha / 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 / 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-REW / Peroxisome proliferator-activated receptor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.35 Å
AuthorsMuckelbauer, J.
CitationJournal: To be Published
Title: Discovery of Azetidinone Acids as Conformationally-Constrained Dual (alpha/gamma) PPAR Activators
Authors: Wang, W. / Devasthale, P. / Farrelly, D. / Gu, L. / Peters, A. / Harrity, T. / Cap, M. / Chu, C. / Kunselman, L. / Morgan, N. / Ponticiello, R. / Zebo, R. / Zhang, L. / Locke, K. / Lippy, J. ...Authors: Wang, W. / Devasthale, P. / Farrelly, D. / Gu, L. / Peters, A. / Harrity, T. / Cap, M. / Chu, C. / Kunselman, L. / Morgan, N. / Ponticiello, R. / Zebo, R. / Zhang, L. / Locke, K. / Lippy, J. / O'Malley, K. / Hosagrahara, V. / Zhang, L. / Kadiyala, P. / Chang, C.Y. / Muckelbauer, J. / Zahler, R. / Hariharan, N. / Ryono, D. / Cheng, P.T.W.
History
DepositionSep 27, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Feb 21, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _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
Revision 1.4Apr 3, 2024Group: Refinement description / Category: 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 alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6913
Polymers31,3161
Non-polymers1,3752
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.264, 78.264, 98.715
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Components on special symmetry positions
IDModelComponents
11A-514-

HOH

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Components

#1: Protein Peroxisome proliferator-activated receptor alpha / PPAR-alpha


Mass: 31316.445 Da / Num. of mol.: 1 / Fragment: ligand binding domain, residues 196-468
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARA, NR1C1, PPAR / Plasmid: PET28A / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21 (DE3) / References: UniProt: Q07869
#2: Chemical ChemComp-CPQ / N,N-BIS(3-D-GLUCONAMIDOPROPYL)DEOXYCHOLAMIDE / DEOXY-BIGCHAP


Mass: 862.056 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H75N3O15 / Comment: detergent*YM
#3: Chemical ChemComp-REW / (2S,3S)-1-(4-METHOXYPHENYL)-3-(3-(2-(5-METHYL-2-PHENYLOXAZOL-4-YL)ETHOXY)BENZYL)-4-OXOAZETIDINE-2-CARBOXYLIC ACID / 4-[2-(3-{[(2S,3S)-2-carboxy-1-(4-methoxyphenyl)-4-oxoazetidin-3-yl]methyl}phenoxy)ethyl]-5-methyl-2-phenyl-1,3-oxazol-3 -ium


Mass: 512.553 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H28N2O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 2.79 Å3/Da / Density % sol: 55.86 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 24, 2003
RadiationMonochromator: Si-111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionRedundancy: 5.7 % / Av σ(I) over netI: 8.2 / Number: 160376 / Rmerge(I) obs: 0.08 / Χ2: 1.12 / D res high: 2.35 Å / D res low: 50 Å / Num. obs: 28240 / % possible obs: 99.7
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
5.06509710.0411.3785.7
4.025.0610010.0481.5365.7
3.514.0210010.0641.4885.7
3.193.5110010.0961.3795.7
2.963.1910010.1391.1075.7
2.792.9610010.1940.9835.7
2.652.7910010.2560.8755.7
2.532.6510010.3450.8635.7
2.432.5310010.4350.8585.6
2.352.4310010.5330.755.6
ReflectionResolution: 2.35→50 Å / Num. obs: 28240 / % possible obs: 99.7 % / Redundancy: 5.7 % / Rmerge(I) obs: 0.08 / Χ2: 1.123 / Net I/σ(I): 8.2
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.533 / Num. unique all: 2839 / Χ2: 0.75 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å30.66 Å
Translation3 Å30.66 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3data extraction
ADSCQuantumdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Previously determined in house PPARalpha LBD structure

Resolution: 2.35→30.66 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.918 / SU B: 6.541 / SU ML: 0.158 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.291 / ESU R Free: 0.227 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.245 759 5 %RANDOM
Rwork0.197 ---
obs0.199 15043 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 45.714 Å2
Baniso -1Baniso -2Baniso -3
1-0.74 Å20.37 Å20 Å2
2--0.74 Å20 Å2
3----1.1 Å2
Refinement stepCycle: LAST / Resolution: 2.35→30.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2003 0 63 98 2164
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222108
X-RAY DIFFRACTIONr_angle_refined_deg1.7192.0122851
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3385252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.82524.59887
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.92615376
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.692159
X-RAY DIFFRACTIONr_chiral_restr0.1030.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021523
X-RAY DIFFRACTIONr_nbd_refined0.2110.21063
X-RAY DIFFRACTIONr_nbtor_refined0.3060.21481
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1710.2118
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2160.231
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.070.25
X-RAY DIFFRACTIONr_mcbond_it1.13321313
X-RAY DIFFRACTIONr_mcangle_it1.8462.52045
X-RAY DIFFRACTIONr_scbond_it2.0053890
X-RAY DIFFRACTIONr_scangle_it3.1484.5804
LS refinement shellResolution: 2.35→2.405 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.319 51 -
Rwork0.225 1005 -
all-1056 -
obs--100 %

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