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- PDB-2p4y: Crystal structure of human PPAR-gamma-ligand binding domain compl... -

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Basic information

Entry
Database: PDB / ID: 2p4y
TitleCrystal structure of human PPAR-gamma-ligand binding domain complexed with an indole-based modulator
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / NUCLEAR RECEPTOR / LIGAND BINDING DOMAIN / LBD / ALPHA HELIX SANDWICH / PPAR-HOMODIMER / SPPARgM / PARTIAL AGONIST
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 / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type ...Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / 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-C03 / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsMcKeever, B.M.
CitationJournal: Mol.Pharmacol. / Year: 2008
Title: The differential interactions of peroxisome proliferator-activated receptor gamma ligands with Tyr473 is a physical basis for their unique biological activities.
Authors: Einstein, M. / Akiyama, T.E. / Castriota, G.A. / Wang, C.F. / McKeever, B. / Mosley, R.T. / Becker, J.W. / Moller, D.E. / Meinke, P.T. / Wood, H.B. / Berger, J.P.
History
DepositionMar 13, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 8, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model
Remark 300 BIOMOLECULE: 1 THIS ENTRY CONTAINS THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT WHICH CONSISTS OF 2 CHAINS. ... BIOMOLECULE: 1 THIS ENTRY CONTAINS THE CRYSTALLOGRAPHIC ASYMMETRIC UNIT WHICH CONSISTS OF 2 CHAINS. SEE REMARK 350 FOR INFORMATION ON GENERATING THE BIOLOGICAL MOLECULE. AUTHORS STATE THAT A PPARGAMMA HOMODIMER IS AN ARTIFACT OF CRYSTALLIZATION WHICH MAY SERVE AS A MODEL FOR AN ASSEMBLY OF THE BIOLOGICALLY IMPORTANT HETERODIMER PPAR-RXR.
Remark 999 SEQUENCE AUTHORS STATE THAT RESIDUES GLY 201 AND SER 202 IN CHAINS A AND B ARE THE REMNANTS OF A ... SEQUENCE AUTHORS STATE THAT RESIDUES GLY 201 AND SER 202 IN CHAINS A AND B ARE THE REMNANTS OF A THROMBIN-CLEAVAGE SITE BETWEEN GLUTATHIONE-S-TRANSFERASE AND PPARGAMMA-LBD.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)64,4595
Polymers63,1872
Non-polymers1,2723
Water1,67593
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.148, 59.859, 118.287
Angle α, β, γ (deg.)90.00, 103.76, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 31593.648 Da / Num. of mol.: 2 / Fragment: Ligand-binding Domain (LBD), Residues 231-505
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pGEX4T2 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P37231
#2: Chemical ChemComp-C03 / (2R)-2-(4-CHLORO-3-{[3-(6-METHOXY-1,2-BENZISOXAZOL-3-YL)-2-METHYL-6-(TRIFLUOROMETHOXY)-1H-INDOL-1-YL]METHYL}PHENOXY)PROPANOIC ACID


Mass: 574.932 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H22ClF3N2O6
#3: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#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: 2.52 Å3/Da / Density % sol: 51.15 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.95M Trisodium citrate, 0.1M Tris-HCl pH 8.5, 1mM TCEP, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Apr 27, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.25→40.34 Å / Num. all: 29974 / Num. obs: 29681 / % possible obs: 99 % / Redundancy: 5 % / Biso Wilson estimate: 29.6 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 15.6
Reflection shellResolution: 2.25→2.35 Å / Rmerge(I) obs: 0.3533 / Mean I/σ(I) obs: 2.51 / Num. unique all: 3407 / % possible all: 93.7

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Processing

Software
NameVersionClassification
CNX2005refinement
ADSCQuantumdata collection
HKL-2000data reduction
SCALEPACKdata scaling
CNX2005phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: SE-MET PPAR-GAMMA-LBD COMPLEX

Resolution: 2.25→40.34 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 169416.6 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: Maximum likelihood function based on F
RfactorNum. reflection% reflectionSelection details
Rfree0.274 1402 4.9 %RANDOM
Rwork0.232 ---
all0.232 28327 --
obs0.232 28327 94.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 45.4658 Å2 / ksol: 0.369776 e/Å3
Displacement parametersBiso mean: 43.5 Å2
Baniso -1Baniso -2Baniso -3
1--8.41 Å20 Å22.34 Å2
2--9.36 Å20 Å2
3----0.95 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.37 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.37 Å0.42 Å
Refinement stepCycle: LAST / Resolution: 2.25→40.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3792 0 88 93 3973
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d20.6
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_mcbond_it1.451.5
X-RAY DIFFRACTIONc_mcangle_it2.32
X-RAY DIFFRACTIONc_scbond_it2.232
X-RAY DIFFRACTIONc_scangle_it3.372.5
LS refinement shellResolution: 2.25→2.39 Å / Rfactor Rfree error: 0.026 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.383 210 5.1 %
Rwork0.324 3890 -
obs-4100 82.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.pprotein.top
X-RAY DIFFRACTION2water_rep.parwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4tri.partri.top
X-RAY DIFFRACTION5C02.parC02.top

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