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- PDB-8rce: Crystal structure of PPAR alfa Ligand Binding Domain in complex w... -

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Basic information

Entry
Database: PDB / ID: 8rce
TitleCrystal structure of PPAR alfa Ligand Binding Domain in complex with the ligand LBB78
ComponentsPeroxisome proliferator-activated receptor alpha
KeywordsTRANSCRIPTION / Nucelar receptors / PPARs
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 / regulation of ketone metabolic process / cellular response to fructose stimulus / regulation of fatty acid metabolic process / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / lipoprotein metabolic process ...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 / regulation of ketone metabolic process / cellular response to fructose stimulus / regulation of fatty acid metabolic process / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / lipoprotein metabolic process / positive regulation of fatty acid oxidation / behavioral response to nicotine / negative regulation of hepatocyte apoptotic process / negative regulation of leukocyte cell-cell adhesion / mitogen-activated protein kinase kinase kinase binding / ubiquitin conjugating enzyme binding / negative regulation of glycolytic process / positive regulation of fatty acid metabolic process / DNA-binding transcription activator activity / nuclear steroid receptor activity / positive regulation of ATP biosynthetic process / NFAT protein binding / negative regulation of cholesterol storage / negative regulation of macrophage derived foam cell differentiation / epidermis development / phosphatase binding / positive regulation of lipid biosynthetic process / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / intracellular receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / nitric oxide metabolic process / negative regulation of blood pressure / hormone-mediated signaling pathway / : / MDM2/MDM4 family protein binding / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / negative regulation of cytokine production involved in inflammatory response / response to nutrient / positive regulation of gluconeogenesis / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / BMAL1:CLOCK,NPAS2 activates circadian expression / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / cellular response to starvation / gluconeogenesis / fatty acid metabolic process / response to insulin / SUMOylation of intracellular receptors / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / wound healing / Heme signaling / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / PPARA activates gene expression / regulation of circadian rhythm / Cytoprotection by HMOX1 / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / nuclear receptor activity / : / heart development / DNA-binding transcription activator activity, RNA polymerase II-specific / gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / response to ethanol / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / response to hypoxia / protein domain specific binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / 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 / : / 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 ...Peroxisome proliferator-activated receptor alpha / Peroxisome proliferator-activated 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
Similarity search - Domain/homology
: / Peroxisome proliferator-activated receptor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsCapelli, D. / Montanari, R.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier ...Title: A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.
Authors: Laghezza, A. / Cerchia, C. / Genovese, M. / Montanari, R. / Capelli, D. / Wackerlig, J. / Simic, S. / Falbo, E. / Pecora, L. / Leuci, R. / Brunetti, L. / Piemontese, L. / Tortorella, P. / ...Authors: Laghezza, A. / Cerchia, C. / Genovese, M. / Montanari, R. / Capelli, D. / Wackerlig, J. / Simic, S. / Falbo, E. / Pecora, L. / Leuci, R. / Brunetti, L. / Piemontese, L. / Tortorella, P. / Biswas, A. / Singh, R.P. / Tambe, S. / Sudeep, C.A. / Pattnaik, A.K. / Jayaprakash, V. / Paoli, P. / Lavecchia, A. / Loiodice, F.
History
DepositionDec 6, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release

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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)32,6202
Polymers32,2521
Non-polymers3681
Water1,36976
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12320 Å2
Unit cell
Length a, b, c (Å)62.280, 62.280, 125.540
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-624-

HOH

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Components

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


Mass: 32251.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARA, NR1C1, PPAR / Production host: Escherichia coli (E. coli) / References: UniProt: Q07869
#2: Chemical ChemComp-WUE / (2~{S})-2-(4-naphthalen-1-ylphenoxy)-3-phenyl-propanoic acid


Mass: 368.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H20O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationN

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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

Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 20 % PEG 3350, 0.2 M Mg acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Jul 2, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 3→55.79 Å / Num. obs: 5774 / % possible obs: 99.7 % / Redundancy: 8.9 % / Rmerge(I) obs: 0.172 / Rrim(I) all: 0.193 / Net I/σ(I): 8.5
Reflection shellResolution: 3.1→3.1 Å / Rmerge(I) obs: 1.771 / Num. unique obs: 888

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→55.79 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.918 / SU B: 33.99 / SU ML: 0.556 / Cross valid method: THROUGHOUT / ESU R Free: 0.614 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.29981 569 10.6 %RANDOM
Rwork0.2294 ---
obs0.23636 4789 99.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1 Å / Solvent model: MASK
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.41 Å20 Å20 Å2
2---0.41 Å2-0 Å2
3---0.81 Å2
Refinement stepCycle: 1 / Resolution: 3→55.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2037 0 28 76 2141
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0122103
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6211.6492832
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.75252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.15123.465101
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.16415394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.107159
X-RAY DIFFRACTIONr_chiral_restr0.1080.2274
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021540
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it9.6849.8151017
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it14.7414.6781266
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it12.59710.4011084
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined24.478986
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.001→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.423 39 -
Rwork0.362 338 -
obs--99.74 %

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