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Basic information

Entry
Database: PDB / ID: 2hwq
TitleStructural basis for the structure-activity relationships of Peroxisome Proliferator-Activated Receptor agonists
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsLIGAND BINDING PROTEIN / PPAR
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-DRY / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsPeng, Y.H. / Lu, I.L. / Mahindroo, N. / Lin, C.H. / Hsieh, H.P. / Wu, S.Y.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Structural basis for the structure-activity relationships of peroxisome proliferator-activated receptor agonists
Authors: Mahindroo, N. / Peng, Y.H. / Lin, C.H. / Tan, U.K. / Prakash, E. / Lien, T.W. / Lu, I.L. / Lee, H.J. / Hsu, J.T.A. / Chen, X. / Liao, C.C. / Lyu, P.C. / Chao, Y.S. / Wu, S.Y. / Hsieh, H.P.
History
DepositionAug 1, 2006Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Aug 7, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)62,5163
Polymers61,9942
Non-polymers5221
Water3,513195
1
A: Peroxisome proliferator-activated receptor gamma
B: Peroxisome proliferator-activated receptor gamma
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)125,0316
Polymers123,9884
Non-polymers1,0432
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_456-x-1,y+1/2,-z+11
Unit cell
Length a, b, c (Å)56.015, 88.671, 58.024
Angle α, β, γ (deg.)90.00, 90.24, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 30997.021 Da / Num. of mol.: 2 / Fragment: Ligand binding domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pGEX6P-1 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P37231
#2: Chemical ChemComp-DRY / [(1-{3-[(6-BENZOYL-1-PROPYL-2-NAPHTHYL)OXY]PROPYL}-1H-INDOL-5-YL)OXY]ACETIC ACID / {1-[3-(6-BENZOYL-1-PROPYLNAPHTHALEN-2-YLOXY)PROPYL]-1H-INDOL-5-YLOXY}-ACETIC ACID


Mass: 521.603 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H31NO5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 195 / 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: 2.13 Å3/Da / Density % sol: 47.07 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 28.25% PEG3350, 0.016M sodium citrate, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13B1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 24, 2006
RadiationMonochromator: Monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.97→50 Å / Num. obs: 40346 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 1.97→1.97 Å / % possible all: 100

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Processing

Software
NameClassification
SHELXmodel building
SHELXL-97refinement
HKL-2000data collection
HKL-2000data reduction
SCALEPACKdata scaling
SHELXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ATH

2ath


Resolution: 1.97→30 Å / Num. parameters: 18391 / Num. restraintsaints: 17885 / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2646 2018 0 %RANDOM
Rwork0.2391 ---
all0.2506 ---
obs0.2391 40346 --
Refine analyzeNum. disordered residues: 0 / Occupancy sum hydrogen: 0 / Occupancy sum non hydrogen: 4597
Refinement stepCycle: LAST / Resolution: 1.97→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4113 0 39 195 4347
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.011
X-RAY DIFFRACTIONs_angle_d0.023
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.0214
X-RAY DIFFRACTIONs_zero_chiral_vol0.033
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.07
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.105
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.037
X-RAY DIFFRACTIONs_approx_iso_adps0

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