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- PDB-6ilq: Crystal structure of PPARgamma with compound BR101549 -

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Basic information

Entry
Database: PDB / ID: 6ilq
TitleCrystal structure of PPARgamma with compound BR101549
Components
  • Nuclear receptor coactivator 1
  • Peroxisome proliferator-activated receptor gamma
KeywordsNUCLEAR PROTEIN / peroxisome proliferator-activated receptor-g(PPAR-g) / transcription factor / ligand-binding domain / Steroid receptor Coactivator-1
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 / positive regulation of female receptivity / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / beige fat cell differentiation ...labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / beige fat cell differentiation / negative regulation of vascular endothelial cell proliferation / positive regulation of cholesterol transport / negative regulation of cellular response to transforming growth factor beta stimulus / arachidonate binding / positive regulation of adiponectin secretion / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / white fat cell differentiation / DNA binding domain binding / positive regulation of vascular associated smooth muscle cell apoptotic process / negative regulation of cardiac muscle hypertrophy in response to stress / positive regulation of lipid metabolic process / STAT family protein binding / positive regulation of fatty acid metabolic process / WW domain binding / hypothalamus development / negative regulation of type II interferon-mediated signaling pathway / male mating behavior / LBD domain binding / negative regulation of cholesterol storage / lipid homeostasis / response to lipid / positive regulation of lipoprotein transport / negative regulation of SMAD protein signal transduction / E-box binding / progesterone receptor signaling pathway / cellular response to Thyroglobulin triiodothyronine / R-SMAD binding / Synthesis of bile acids and bile salts / monocyte differentiation / brown fat cell differentiation / negative regulation of blood vessel endothelial cell migration / negative regulation of BMP signaling pathway / cell fate commitment / negative regulation of vascular associated smooth muscle cell proliferation / alpha-actinin binding / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / BMP signaling pathway / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / positive regulation of cholesterol efflux / Endogenous sterols / positive regulation of fat cell differentiation / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / cellular response to low-density lipoprotein particle stimulus / response to retinoic acid / fat cell differentiation / long-chain fatty acid transport / protein-lysine-acetyltransferase activity / negative regulation of mitochondrial fission / negative regulation of osteoblast differentiation / nuclear retinoid X receptor binding / estrous cycle / cell maturation / retinoic acid receptor signaling pathway / Recycling of bile acids and salts / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / histone acetyltransferase / lactation / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / cellular response to hormone stimulus / intracellular receptor signaling pathway / negative regulation of MAPK cascade / peroxisome proliferator activated receptor signaling pathway / hormone-mediated signaling pathway / Regulation of lipid metabolism by PPARalpha / response to progesterone / cerebellum development / positive regulation of adipose tissue development / peptide binding / positive regulation of neuron differentiation / epithelial cell differentiation / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian expression / regulation of cellular response to insulin stimulus / placenta development / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / negative regulation of miRNA transcription / fatty acid metabolic process / negative regulation of angiogenesis / positive regulation of apoptotic signaling pathway / nuclear estrogen receptor binding / nuclear receptor binding / hippocampus development / Regulation of PTEN gene transcription / transcription coregulator binding / negative regulation of smooth muscle cell proliferation
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 / Nuclear receptor coactivators bHLH domain / 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 / 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-AE0 / Peroxisome proliferator-activated receptor gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.408 Å
AuthorsHong, E. / Jang, T.H. / Chin, J. / Kim, K.H. / Jung, W. / Kim, S.H.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Identification of BR101549 as a lead candidate of non-TZD PPAR gamma agonist for the treatment of type 2 diabetes: Proof-of-concept evaluation and SAR.
Authors: Choung, W. / Jung, H.J. / Yang, D. / Nam, E.H. / Choi, H. / Lee, B.R. / Park, M. / Jang, S.M. / Lim, J.S. / Kim, W.S. / Kim, K.H. / Chin, J. / Jung, K. / Lee, G. / Hong, E. / Jang, T.H. / Myung, J. / Kim, S.H.
History
DepositionOct 19, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 11, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4313
Polymers33,9002
Non-polymers5311
Water1,13563
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1260 Å2
ΔGint-13 kcal/mol
Surface area12440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.647, 85.257, 122.844
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-657-

HOH

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Components

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


Mass: 31094.135 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 Nuclear receptor coactivator 1 / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal ...NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal carcinoma antigen NY-REN-52 / Steroid receptor coactivator 1 / SRC-1


Mass: 2806.163 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-AE0 / ethyl [2-butyl-6-oxo-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]methyl}-4-(propan-2-yl)-1,6-dihydropyrimidin-5-yl]acetate


Mass: 530.615 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H34N4O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 2.07 Å3/Da / Density % sol: 40.63 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 0.2 M MgCl2, 0.1 M TRIS 8.5 pH, 27 %w/v PEG 3350

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Data collection

DiffractionMean temperature: 277 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 6B / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 11, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.408→25.44 Å / Num. obs: 10939 / % possible obs: 97.25 % / Redundancy: 6.4 % / CC1/2: 0.995 / Rmerge(I) obs: 0.09336 / Rpim(I) all: 0.04269 / Rrim(I) all: 0.1031 / Net I/σ(I): 30.5
Reflection shellResolution: 2.408→2.494 Å / Rmerge(I) obs: 0.3838 / Num. unique obs: 1040 / CC1/2: 0.973 / Rpim(I) all: 0.1532

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260: ???)refinement
HKL-2000data collection
HKL-2000data scaling
PHENIXmodel building
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3KMG

3kmg


Resolution: 2.408→25.439 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 30.35
RfactorNum. reflection% reflection
Rfree0.3035 1097 10.03 %
Rwork0.2157 --
obs0.2238 10936 97.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.408→25.439 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2037 0 39 63 2139
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082120
X-RAY DIFFRACTIONf_angle_d0.9122863
X-RAY DIFFRACTIONf_dihedral_angle_d5.9661740
X-RAY DIFFRACTIONf_chiral_restr0.047337
X-RAY DIFFRACTIONf_plane_restr0.004355
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4076-2.51710.33961430.25311175X-RAY DIFFRACTION96
2.5171-2.64960.32451310.24381245X-RAY DIFFRACTION100
2.6496-2.81540.34381460.24351242X-RAY DIFFRACTION100
2.8154-3.03250.33731350.25051242X-RAY DIFFRACTION100
3.0325-3.33710.33291430.22911269X-RAY DIFFRACTION100
3.3371-3.81860.29261340.19861261X-RAY DIFFRACTION100
3.8186-4.80570.24831390.17631237X-RAY DIFFRACTION97
4.8057-25.440.30791260.22851168X-RAY DIFFRACTION87
Refinement TLS params.Method: refined / Origin x: -21.5237 Å / Origin y: -9.5726 Å / Origin z: 15.3419 Å
111213212223313233
T0.3612 Å20.0084 Å20.0054 Å2-0.378 Å20.0313 Å2--0.2472 Å2
L3.8505 °20.7414 °20.8796 °2-3.8432 °21.4744 °2--2.8779 °2
S-0.0296 Å °0.1255 Å °-0.1139 Å °0.0295 Å °0.1744 Å °-0.1145 Å °0.2051 Å °0.2734 Å °-0.1412 Å °
Refinement TLS groupSelection details: all

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