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- PDB-5xmx: Co-crystal structure of Inhibitor compound in complex with human ... -

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Basic information

Entry
Database: PDB / ID: 5xmx
TitleCo-crystal structure of Inhibitor compound in complex with human PPARdelta LBD
ComponentsPeroxisome proliferator-activated receptor delta
KeywordsTRANSCRIPTION/INHIBITOR / PPARdelta / Inhibitor compound / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


fat cell proliferation / positive regulation of fat cell proliferation / keratinocyte migration / linoleic acid binding / positive regulation of skeletal muscle tissue regeneration / positive regulation of epidermis development / axon ensheathment / regulation of skeletal muscle satellite cell proliferation / D-glucose transmembrane transport / negative regulation of smooth muscle cell migration ...fat cell proliferation / positive regulation of fat cell proliferation / keratinocyte migration / linoleic acid binding / positive regulation of skeletal muscle tissue regeneration / positive regulation of epidermis development / axon ensheathment / regulation of skeletal muscle satellite cell proliferation / D-glucose transmembrane transport / negative regulation of smooth muscle cell migration / positive regulation of myoblast proliferation / proteoglycan metabolic process / fatty acid catabolic process / negative regulation of collagen biosynthetic process / positive regulation of fatty acid oxidation / phospholipid biosynthetic process / Carnitine shuttle / negative regulation of myoblast differentiation / response to vitamin A / Signaling by Retinoic Acid / positive regulation of fatty acid metabolic process / nuclear steroid receptor activity / fatty acid beta-oxidation / negative regulation of cholesterol storage / cell-substrate adhesion / positive regulation of insulin secretion involved in cellular response to glucose stimulus / decidualization / keratinocyte proliferation / positive regulation of fat cell differentiation / adipose tissue development / NF-kappaB binding / cellular response to nutrient levels / fatty acid transport / response to glucose / energy homeostasis / intracellular receptor signaling pathway / hormone-mediated signaling pathway / embryo implantation / cholesterol metabolic process / negative regulation of miRNA transcription / response to activity / fatty acid metabolic process / generation of precursor metabolites and energy / phosphatidylinositol 3-kinase/protein kinase B signal transduction / apoptotic signaling pathway / negative regulation of smooth muscle cell proliferation / wound healing / transcription coactivator binding / negative regulation of cell growth / Nuclear Receptor transcription pathway / lipid metabolic process / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / nuclear receptor activity / glucose metabolic process / negative regulation of epithelial cell proliferation / sequence-specific double-stranded DNA binding / vasodilation / heart development / cellular response to lipopolysaccharide / cellular response to hypoxia / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / cell population proliferation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / apoptotic process / lipid binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / 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, beta / 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 / Double treble clef zinc finger, C4 type / Nuclear hormone receptors DNA-binding domain profile. ...Peroxisome proliferator-activated receptor, beta / 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 / 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-89L / Peroxisome proliferator-activated receptor delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsLakshminarasimhan, A. / Rani, S.T. / Senaiar, R.S. / Krishnamurthy, N.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Novel highly selective peroxisome proliferator-activated receptor delta (PPAR delta) modulators with pharmacokinetic properties suitable for once-daily oral dosing.
Authors: Lagu, B. / Kluge, A.F. / Fredenburg, R.A. / Tozzo, E. / Senaiar, R.S. / Jaleel, M. / Panigrahi, S.K. / Tiwari, N.K. / Krishnamurthy, N.R. / Takahashi, T. / Patane, M.A.
History
DepositionMay 16, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 23, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Peroxisome proliferator-activated receptor delta
B: Peroxisome proliferator-activated receptor delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,7284
Polymers62,8612
Non-polymers8672
Water3,999222
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area730 Å2
ΔGint-4 kcal/mol
Surface area24010 Å2
Unit cell
Length a, b, c (Å)39.840, 76.390, 96.730
Angle α, β, γ (deg.)90.00, 97.74, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Peroxisome proliferator-activated receptor delta / PPAR-delta / NUCI / Nuclear hormone receptor 1 / NUC1 / Nuclear receptor subfamily 1 group C member ...PPAR-delta / NUCI / Nuclear hormone receptor 1 / NUC1 / Nuclear receptor subfamily 1 group C member 2 / Peroxisome proliferator-activated receptor beta / PPAR-beta


Mass: 31430.535 Da / Num. of mol.: 2 / Fragment: UNP residues 171-441
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARD, NR1C2, PPARB / Plasmid: pET28a-PPAR / Details (production host): pET28a-PPAR / Production host: Escherichia coli (E. coli) / References: UniProt: Q03181
#2: Chemical ChemComp-89L / (E)-6-[2-[[[4-(furan-2-yl)phenyl]carbonyl-methyl-amino]methyl]phenoxy]-4-methyl-hex-4-enoic acid


Mass: 433.496 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H27NO5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 222 / 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: 2.36 Å3/Da / Density % sol: 47.85 % / Description: Long rod shaped
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 40mM Bis-Tris-propane (pH 8.0), 20% (w/v) polyethylene glycol (PEG) 8000, 200mM KCl, 6% propanol, 1mM CaCl2, 5% n-Octyl-b-D-thioglucoside
PH range: 8-8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.71073 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 19, 2014
RadiationMonochromator: 'Silicon Double Crystal' / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.71073 Å / Relative weight: 1
ReflectionResolution: 2→95.84 Å / Num. obs: 62049 / % possible obs: 99.2 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.042 / Net I/σ(I): 11.2
Reflection shellResolution: 1.74→1.81 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.601 / Mean I/σ(I) obs: 1.5 / % possible all: 96.5

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
XDSdata processing
XDSdata reduction
XDSdata scaling
SCALEPACK1data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TKM

3tkm


Resolution: 2→38.37 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.892 / SU B: 4.517 / SU ML: 0.13 / Cross valid method: THROUGHOUT / ESU R: 0.214 / ESU R Free: 0.203 / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.28181 1849 4.9 %RANDOM
Rwork0.21211 ---
obs0.2155 35806 96.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 32.579 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å20 Å20 Å2
2--0.02 Å2-0 Å2
3---0.04 Å2
Refinement stepCycle: 1 / Resolution: 2→38.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4049 0 64 222 4335
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0194251
X-RAY DIFFRACTIONr_bond_other_d0.0020.0248
X-RAY DIFFRACTIONr_angle_refined_deg1.9141.9825743
X-RAY DIFFRACTIONr_angle_other_deg1.1373102
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1695502
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.40424.011187
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.80515760
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4161522
X-RAY DIFFRACTIONr_chiral_restr0.1410.2649
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0213154
X-RAY DIFFRACTIONr_gen_planes_other0.0010.0222
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
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: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 135 -
Rwork0.21 2616 -
obs--96.19 %

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