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- PDB-2gtk: Structure-based Design of Indole Propionic Acids as Novel PPARag ... -

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Basic information

Entry
Database: PDB / ID: 2gtk
TitleStructure-based Design of Indole Propionic Acids as Novel PPARag CO-Agonists
Components
  • Decamer from Nuclear receptor coactivator 1
  • Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION REGULATOR / NUCLEAR RECEPTOR
Function / homology
Function and homology information


labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / positive regulation of female receptivity / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation ...labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / positive regulation of female receptivity / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation / positive regulation of cholesterol transport / negative regulation of cardiac muscle hypertrophy in response to stress / negative regulation of cellular response to transforming growth factor beta stimulus / positive regulation of low-density lipoprotein receptor activity / arachidonate binding / positive regulation of adiponectin secretion / lipoprotein transport / negative regulation of sequestering of triglyceride / DNA binding domain binding / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / STAT family protein binding / WW domain binding / positive regulation of fatty acid metabolic process / hypothalamus development / male mating behavior / response to lipid / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of SMAD protein signal transduction / LBD domain binding / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / E-box binding / alpha-actinin binding / lipid homeostasis / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of blood vessel endothelial cell migration / negative regulation of macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / negative regulation of lipid storage / cellular response to Thyroglobulin triiodothyronine / white fat cell differentiation / negative regulation of BMP signaling pathway / Synthesis of bile acids and bile salts / positive regulation of cholesterol efflux / negative regulation of mitochondrial fission / estrous cycle / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / cell fate commitment / negative regulation of MAPK cascade / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / BMP signaling pathway / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / retinoic acid receptor signaling pathway / progesterone receptor signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / histone acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / cell maturation / cellular response to hormone stimulus / negative regulation of signaling receptor activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / epithelial cell differentiation / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / negative regulation of angiogenesis / cerebellum development / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian gene expression / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Regulation of PTEN gene transcription / transcription coregulator binding / response to progesterone / fatty acid metabolic process / nuclear receptor binding / nuclear estrogen receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / positive regulation of apoptotic signaling pathway / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / peptide binding
Similarity search - Function
Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator ...Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / : / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / PAS domain superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / 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-208 / Peroxisome proliferator-activated receptor gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsKuhn, B. / Hilpert, H. / Benz, J. / Binggeli, A. / Grether, U. / Humm, R. / Maerki, H.-P. / Meyer, M. / Mohr, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists
Authors: Kuhn, B. / Hilpert, H. / Benz, J. / Binggeli, A. / Grether, U. / Humm, R. / Meyer, M. / Mohr, P.
History
DepositionApr 28, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 26, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Revision 1.4Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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
Revision 1.5Apr 3, 2024Group: Refinement description / Category: 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: Decamer from Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5913
Polymers32,1522
Non-polymers4391
Water4,576254
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-23 kcal/mol
Surface area13140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.239, 68.319, 87.952
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 / PPARg-LBD / PPAR-gamma


Mass: 30997.021 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Production host: Escherichia coli (E. coli) / References: UniProt: P37231
#2: Protein/peptide Decamer from Nuclear receptor coactivator 1


Mass: 1155.386 Da / Num. of mol.: 1 / Fragment: residues 631-640 / Source method: obtained synthetically / Details: this sequence occurs naturally in Homo sapiens / References: UniProt: Q15788
#3: Chemical ChemComp-208 / (2S)-3-(1-{[2-(2-CHLOROPHENYL)-5-METHYL-1,3-OXAZOL-4-YL]METHYL}-1H-INDOL-5-YL)-2-ETHOXYPROPANOIC ACID


Mass: 438.903 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23ClN2O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 254 / 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: 2.53 Å3/Da / Density % sol: 51.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.1M TRIS, PEG 3350, 0.2M MGSO4, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR571 / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Oct 29, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. all: 18856 / Num. obs: 18856 / % possible obs: 94 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.1→2.18 Å / % possible all: 96

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.1.24refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: in house structure of PPARg

Resolution: 2.1→20 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.89 / SU B: 4.74 / SU ML: 0.128 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.234 / ESU R Free: 0.21 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26075 957 5.1 %RANDOM
Rwork0.19522 ---
obs0.19848 17716 95.07 %-
all-18856 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 29.397 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å20 Å20 Å2
2--1.45 Å20 Å2
3----1.07 Å2
Refinement stepCycle: LAST / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2149 0 31 254 2434
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222217
X-RAY DIFFRACTIONr_angle_refined_deg1.372.0032988
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5135265
X-RAY DIFFRACTIONr_chiral_restr0.0890.2347
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021607
X-RAY DIFFRACTIONr_nbd_refined0.2040.21129
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1680.2240
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0980.217
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1190.213
X-RAY DIFFRACTIONr_mcbond_it0.7181.51337
X-RAY DIFFRACTIONr_mcangle_it1.40122164
X-RAY DIFFRACTIONr_scbond_it2.2393880
X-RAY DIFFRACTIONr_scangle_it3.8254.5824
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.27 66
Rwork0.206 1281

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