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- PDB-6vzm: Crystal structure of human PPARgamma ligand binding domain Y473E ... -

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Basic information

Entry
Database: PDB / ID: 6vzm
TitleCrystal structure of human PPARgamma ligand binding domain Y473E mutant in complex with Darglitazone
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / Nuclear receptors / TZDs / Drug design / Therapeutic targets
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 / positive regulation of fatty acid metabolic process / STAT family protein binding / response to lipid / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / negative regulation of cholesterol storage / negative regulation of SMAD protein signal transduction / lipid homeostasis / E-box binding / alpha-actinin binding / R-SMAD binding / negative regulation of vascular associated smooth muscle cell proliferation / monocyte differentiation / negative regulation of blood vessel endothelial cell migration / white fat cell differentiation / cellular response to low-density lipoprotein particle stimulus / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / negative regulation of BMP signaling pathway / positive regulation of cholesterol efflux / cell fate commitment / negative regulation of osteoblast differentiation / negative regulation of mitochondrial fission / positive regulation of fat cell differentiation / 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 / negative regulation of MAPK cascade / intracellular receptor signaling pathway / hormone-mediated signaling pathway / positive regulation of adipose tissue development / response to nutrient / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / peptide binding / negative regulation of miRNA transcription / negative regulation of angiogenesis / placenta development / Regulation of PTEN gene transcription / positive regulation of apoptotic signaling pathway / transcription coregulator binding / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / mRNA transcription by RNA polymerase II / negative regulation of transforming growth factor beta receptor signaling pathway / PPARA activates gene expression / fatty acid metabolic process / regulation of circadian rhythm / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / lipid metabolic process / positive regulation of miRNA transcription / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / regulation of blood pressure / RNA polymerase II transcription regulator complex / nuclear receptor activity / cellular response to insulin stimulus / rhythmic process / glucose homeostasis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / double-stranded DNA binding / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to hypoxia / DNA-binding transcription factor binding / sequence-specific DNA binding / nucleic acid binding / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / receptor complex / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / innate immune response / 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-GEV / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsShang, J. / Kojetin, D.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK101871 United States
CitationJournal: Structure / Year: 2021
Title: Structural mechanism underlying ligand binding and activation of PPAR gamma.
Authors: Shang, J. / Kojetin, D.J.
History
DepositionFeb 28, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 29, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / 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 gamma
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,6684
Polymers62,8312
Non-polymers8372
Water3,693205
1
A: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8342
Polymers31,4151
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8342
Polymers31,4151
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.071, 61.591, 120.527
Angle α, β, γ (deg.)90.000, 102.170, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Peroxisome proliferator-activated receptor gamma / PPAR-gamma / Nuclear receptor subfamily 1 group C member 3


Mass: 31415.461 Da / Num. of mol.: 2 / Mutation: Y473E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pET46 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P37231
#2: Chemical ChemComp-GEV / (5Z)-5-({4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propanoyl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione / Darglitazone


Mass: 418.465 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H18N2O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / 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: 2.69 Å3/Da / Density % sol: 54.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4 / Details: 0.1M MOPS, pH 7.4, 0.8M SODIUM CITRATE

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 16, 2018
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.4→33.415 Å / Num. obs: 25861 / % possible obs: 98.16 % / Redundancy: 2 % / Biso Wilson estimate: 24.2 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.02448 / Rpim(I) all: 0.02448 / Rrim(I) all: 0.03462 / Net I/σ(I): 13.59
Reflection shellResolution: 2.4→2.486 Å / Redundancy: 2 % / Rmerge(I) obs: 0.3615 / Num. unique obs: 2552 / CC1/2: 0.774 / Rpim(I) all: 0.3615 / % possible all: 98.76

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Processing

Software
NameVersionClassification
SCALAdata scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1PRG

1prg


Resolution: 2.4→33.415 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 28.47
RfactorNum. reflection% reflection
Rfree0.2782 1999 7.74 %
Rwork0.2174 --
obs0.222 25841 98.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 92.32 Å2 / Biso mean: 32.88 Å2 / Biso min: 7.25 Å2
Refinement stepCycle: final / Resolution: 2.4→33.415 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4075 0 60 205 4340
Biso mean--43.47 31.7 -
Num. residues----508
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094284
X-RAY DIFFRACTIONf_angle_d1.1675770
X-RAY DIFFRACTIONf_chiral_restr0.049662
X-RAY DIFFRACTIONf_plane_restr0.007724
X-RAY DIFFRACTIONf_dihedral_angle_d7.3632639
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.4001-2.46010.34311420.283169599
2.4601-2.52660.33661440.2598170899
2.5266-2.6010.29741400.2538167499
2.601-2.68490.30131420.2645169598
2.6849-2.78080.33611410.2497167397
2.7808-2.89210.35351400.2536166398
2.8921-3.02360.32571440.2521732100
3.0236-3.18290.32351410.2464168699
3.1829-3.38210.2821440.2414171098
3.3821-3.6430.27271420.2071168897
3.643-4.0090.28551440.2014172098
4.009-4.58790.21471440.1721171799
4.5879-5.77540.24461430.1852171197
5.7754-33.4150.20181480.1707177098

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