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- PDB-8cph: Crystal structure of PPAR gamma (PPARG) in complex with WY-14643 ... -

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Basic information

Entry
Database: PDB / ID: 8cph
TitleCrystal structure of PPAR gamma (PPARG) in complex with WY-14643 (inactive form)
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsDNA BINDING PROTEIN / PPARg / allosteric inhibitor / orthosteric inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly / negative regulation of connective tissue replacement involved in inflammatory response wound healing / positive regulation of cholesterol transport / negative regulation of cellular response to transforming growth factor beta stimulus / : / arachidonate binding ...prostaglandin receptor activity / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation / negative regulation of extracellular matrix assembly / negative regulation of connective tissue replacement involved in inflammatory response wound healing / positive regulation of cholesterol transport / negative regulation of cellular response to transforming growth factor beta stimulus / : / arachidonate binding / positive regulation of adiponectin secretion / negative regulation of cardiac muscle hypertrophy in response to stress / DNA binding domain binding / lipoprotein transport / positive regulation of vascular associated smooth muscle cell apoptotic process / WW domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / negative regulation of cholesterol storage / lipid homeostasis / E-box binding / alpha-actinin binding / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of blood vessel endothelial cell migration / white fat cell differentiation / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / negative regulation of BMP signaling pathway / positive regulation of cholesterol efflux / negative regulation of mitochondrial fission / cell fate commitment / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / negative regulation of MAPK cascade / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / retinoic acid receptor signaling pathway / cell maturation / intracellular receptor signaling pathway / positive regulation of adipose tissue development / hormone-mediated signaling pathway / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / response to nutrient / negative regulation of miRNA transcription / peptide binding / negative regulation of angiogenesis / transcription coregulator binding / positive regulation of apoptotic signaling pathway / Regulation of PTEN gene transcription / fatty acid metabolic process / placenta development / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / mRNA transcription by RNA polymerase II / PPARA activates gene expression / regulation of circadian rhythm / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / regulation of blood pressure / lipid metabolic process / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / nuclear receptor activity / rhythmic process / glucose homeostasis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / double-stranded DNA binding / DNA-binding transcription factor binding / cellular response to hypoxia / sequence-specific DNA binding / nucleic acid binding / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / receptor complex / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / innate immune response / negative regulation of gene expression / negative regulation of DNA-templated transcription / intracellular membrane-bounded organelle / chromatin binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II
Similarity search - Function
Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / 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. ...Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / 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
Chem-WY1 / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsChaikuad, A. / Merk, D. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Am.Chem.Soc. / Year: 2023
Title: Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPAR gamma Modulation.
Authors: Arifi, S. / Marschner, J.A. / Pollinger, J. / Isigkeit, L. / Heitel, P. / Kaiser, A. / Obeser, L. / Hofner, G. / Proschak, E. / Knapp, S. / Chaikuad, A. / Heering, J. / Merk, D.
History
DepositionMar 2, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 12, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)63,9834
Polymers63,3362
Non-polymers6482
Water64936
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1730 Å2
ΔGint-1 kcal/mol
Surface area27620 Å2
Unit cell
Length a, b, c (Å)62.521, 63.355, 168.355
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 gamma / PPAR-gamma / Nuclear receptor subfamily 1 group C member 3


Mass: 31667.793 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / References: UniProt: P37231
#2: Chemical ChemComp-WY1 / 2-({4-CHLORO-6-[(2,3-DIMETHYLPHENYL)AMINO]PYRIMIDIN-2-YL}SULFANYL)ACETIC ACID


Mass: 323.798 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H14ClN3O2S / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 36 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.63 Å3/Da / Density % sol: 53.27 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 30% PEG 3350, 0.15M sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00002 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 2.4→44.5 Å / Num. obs: 26908 / % possible obs: 99.8 % / Redundancy: 9.6 % / CC1/2: 1 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.02 / Rrim(I) all: 0.063 / Χ2: 1.03 / Net I/σ(I): 17.2
Reflection shellResolution: 2.4→2.51 Å / Redundancy: 9.4 % / Rmerge(I) obs: 1.255 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 3218 / CC1/2: 0.738 / Rpim(I) all: 0.455 / Rrim(I) all: 1.409 / Χ2: 0.91

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→44.54 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.938 / SU B: 24.666 / SU ML: 0.255 / Cross valid method: THROUGHOUT / ESU R: 0.38 / ESU R Free: 0.264 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26341 1298 4.8 %RANDOM
Rwork0.21638 ---
obs0.21886 25555 99.68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 89.352 Å2
Baniso -1Baniso -2Baniso -3
1-3.23 Å20 Å20 Å2
2--1.6 Å2-0 Å2
3----4.83 Å2
Refinement stepCycle: 1 / Resolution: 2.4→44.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4222 0 42 36 4300
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0134347
X-RAY DIFFRACTIONr_bond_other_d0.0030.0164299
X-RAY DIFFRACTIONr_angle_refined_deg1.3261.6395860
X-RAY DIFFRACTIONr_angle_other_deg1.21.5889928
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2225527
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.81824.348207
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.58515839
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6421516
X-RAY DIFFRACTIONr_chiral_restr0.060.2570
X-RAY DIFFRACTIONr_gen_planes_refined0.010.024950
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02922
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_it4.4386.4862114
X-RAY DIFFRACTIONr_mcbond_other4.4376.4892115
X-RAY DIFFRACTIONr_mcangle_it6.4849.7222639
X-RAY DIFFRACTIONr_mcangle_other6.4839.7242640
X-RAY DIFFRACTIONr_scbond_it5.1067.0962233
X-RAY DIFFRACTIONr_scbond_other5.1047.0992234
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.60310.423222
X-RAY DIFFRACTIONr_long_range_B_refined10.02876.1794678
X-RAY DIFFRACTIONr_long_range_B_other10.02876.2014679
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCSNumber: 2000 / Type: tight thermal / Rms dev position: 3.84 Å / Weight position: 0.5
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.406 88 -
Rwork0.339 1850 -
obs--99.54 %
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)
14.9131.2872-1.84081.8504-0.32472.79920.16130.14760.7003-0.07790.0418-0.0527-0.5353-0.0515-0.20310.14050.02960.01030.03260.00660.1471-23.4549-1.07283.7963
22.3291.20610.34736.03312.38963.8465-0.02240.01270.0580.07150.2303-0.80420.12530.737-0.20790.02860.04210.00120.16570.00120.1401-18.2603-9.473936.4195
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A201 - 477
2X-RAY DIFFRACTION2B201 - 459

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