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- PDB-6dgl: Crystal Structure of Human PPARgamma Ligand Binding Domain in Com... -

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Basic information

Entry
Database: PDB / ID: 6dgl
TitleCrystal Structure of Human PPARgamma Ligand Binding Domain in Complex with Darglitazone
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION/TRANSCRIPTION INHIBITOR / Nuclear receptors / TZDs / Drug design / Therapeutic targets / TRANSCRIPTION / TRANSCRIPTION-TRANSCRIPTION INHIBITOR complex
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 / negative regulation of macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / 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 / peroxisome proliferator activated receptor signaling pathway / response to nutrient / 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 / fatty acid metabolic process / PPARA activates gene expression / regulation of circadian rhythm / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / lipid metabolic process / positive regulation of miRNA transcription / regulation of blood pressure / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / 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 / : / 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-GEV / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 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: Proc.Natl.Acad.Sci.USA / Year: 2019
Title: Quantitative structural assessment of graded receptor agonism.
Authors: Shang, J. / Brust, R. / Griffin, P.R. / Kamenecka, T.M. / Kojetin, D.J.
History
DepositionMay 17, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2019Group: Data collection / Database references / Category: citation / citation_author
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
Revision 1.2Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 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 gamma
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,8504
Polymers63,0132
Non-polymers8372
Water7,620423
1
A: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9252
Polymers31,5071
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)31,9252
Polymers31,5071
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.360, 61.740, 119.470
Angle α, β, γ (deg.)90.00, 102.72, 90.00
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: 31506.574 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / 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
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 423 / 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: 2.67 Å3/Da / Density % sol: 53.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.6 / Details: 0.8M SODIUM CITRATE, 100mM MOPS, pH 7.6

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Mar 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.95→41.015 Å / Num. obs: 47271 / % possible obs: 96.06 % / Redundancy: 6.9 % / Net I/σ(I): 94.48
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 7 % / Mean I/σ(I) obs: 3.2 / Num. unique obs: 4544 / % possible all: 94.82

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
SCALAdata scaling
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1PRG

1prg


Resolution: 1.95→41.015 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.1
RfactorNum. reflection% reflection
Rfree0.2685 1989 4.26 %
Rwork0.2224 --
obs0.2244 46646 96.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.95→41.015 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4147 0 60 423 4630
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074280
X-RAY DIFFRACTIONf_angle_d0.9125762
X-RAY DIFFRACTIONf_dihedral_angle_d5.192636
X-RAY DIFFRACTIONf_chiral_restr0.046660
X-RAY DIFFRACTIONf_plane_restr0.005723
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.99880.34141410.33553156X-RAY DIFFRACTION95
1.9988-2.05280.33861370.30263076X-RAY DIFFRACTION95
2.0528-2.11320.34481400.28053132X-RAY DIFFRACTION95
2.1132-2.18140.31121410.2693173X-RAY DIFFRACTION95
2.1814-2.25940.30981400.25073162X-RAY DIFFRACTION96
2.2594-2.34980.26941430.24043204X-RAY DIFFRACTION96
2.3498-2.45680.32321410.23883177X-RAY DIFFRACTION97
2.4568-2.58630.29511440.24023211X-RAY DIFFRACTION97
2.5863-2.74830.2981430.23473215X-RAY DIFFRACTION97
2.7483-2.96040.25291450.21743272X-RAY DIFFRACTION98
2.9604-3.25820.26491450.22023241X-RAY DIFFRACTION98
3.2582-3.72940.26191470.18453301X-RAY DIFFRACTION98
3.7294-4.69760.20021480.16663315X-RAY DIFFRACTION99
4.6976-41.02380.21751340.20733022X-RAY DIFFRACTION88

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