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- PDB-8fkg: Crystal structure of PPARgamma ligand-binding domain in complex w... -

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Basic information

Entry
Database: PDB / ID: 8fkg
TitleCrystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and inverse agonist SR33486
Components
  • Nuclear receptor corepressor 1
  • Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / Nuclear receptors / TZDs / Drug design / Therapeutic targets / transcription-agonist complex
Function / homology
Function and homology information


NR1D1 (REV-ERBA) represses gene expression / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of JNK cascade / prostaglandin receptor activity / regulation of cholesterol transporter activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / negative regulation of glycolytic process / MECP2 regulates transcription factors ...NR1D1 (REV-ERBA) represses gene expression / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of JNK cascade / prostaglandin receptor activity / regulation of cholesterol transporter activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / negative regulation of glycolytic process / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation / negative regulation of cellular response to transforming growth factor beta stimulus / negative regulation of cardiac muscle hypertrophy in response to stress / arachidonic acid binding / positive regulation of low-density lipoprotein receptor activity / nuclear thyroid hormone receptor 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 / negative regulation of fatty acid metabolic process / positive regulation of fatty acid metabolic process / response to lipid / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of SMAD protein signal transduction / Notch-HLH transcription pathway / 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 / locomotor rhythm / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of macrophage derived foam cell differentiation / negative regulation of blood vessel endothelial cell migration / histone deacetylase complex / negative regulation of lipid storage / Regulation of MECP2 expression and activity / cellular response to low-density lipoprotein particle stimulus / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / positive regulation of cholesterol efflux / retinoic acid receptor signaling pathway / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / spindle assembly / cell fate commitment / positive regulation of DNA binding / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Nuclear signaling by ERBB4 / regulation of cellular response to insulin stimulus / cell maturation / negative regulation of signaling receptor activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / epithelial cell differentiation / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / transcription repressor complex / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / negative regulation of angiogenesis / response to nutrient / negative regulation of miRNA transcription / negative regulation of MAP kinase activity / fatty acid metabolic process / Regulation of PTEN gene transcription / transcription coregulator binding / HDACs deacetylate histones / nuclear receptor binding / Downregulation of SMAD2/3:SMAD4 transcriptional activity / peptide binding / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / placenta development / Transcriptional activation of mitochondrial biogenesis / regulation of circadian rhythm / lipid metabolic process / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / mitotic spindle / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / regulation of blood pressure / positive regulation of DNA-binding transcription factor activity / DNA-binding transcription repressor activity, RNA polymerase II-specific / positive regulation of miRNA transcription
Similarity search - Function
N-CoR, GPS2-interacting domain / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / SANT domain / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Myb domain / Myb-like DNA-binding domain / Peroxisome proliferator-activated receptor ...N-CoR, GPS2-interacting domain / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / SANT domain / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Myb domain / Myb-like DNA-binding domain / Peroxisome proliferator-activated receptor / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Homeobox-like 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
Similarity search - Domain/homology
: / : / Nuclear receptor corepressor 1 / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.12 Å
AuthorsMacTavish, B.S. / 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)6R01DK124870 United States
CitationJournal: To Be Published
Title: Crystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and SR33486
Authors: MacTavish, B.S. / Kojetin, D.J.
History
DepositionDec 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
D: Nuclear receptor corepressor 1
A: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,13415
Polymers34,0152
Non-polymers1,11913
Water2,216123
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3020 Å2
ΔGint-5 kcal/mol
Surface area14320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.968, 61.968, 163.608
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-637-

HOH

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Components

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Protein/peptide / Protein , 2 types, 2 molecules DA

#1: Protein/peptide Nuclear receptor corepressor 1 / N-CoR / N-CoR1


Mass: 2508.824 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NCOR1, KIAA1047 / Production host: Escherichia coli (E. coli) / References: UniProt: O75376
#2: Protein Peroxisome proliferator-activated receptor gamma / PPAR-gamma / Nuclear receptor subfamily 1 group C member 3


Mass: 31506.574 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

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Non-polymers , 6 types, 136 molecules

#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-Y62 / 2-chloro-N-(5-cyanopyridin-2-yl)-5-nitrobenzamide


Mass: 302.673 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H7ClN4O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.21 Å3/Da / Density % sol: 44.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2M Ammonium sulfate, 0.1M MES, pH 6.5, 30% w/v, PEG 8000

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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: Jul 21, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.12→30.98 Å / Num. obs: 18917 / % possible obs: 99.9 % / Redundancy: 25.2 % / Biso Wilson estimate: 33.87 Å2 / Rmerge(I) obs: 0.1486 / Net I/σ(I): 29.48
Reflection shellResolution: 2.12→2.195 Å / Redundancy: 26.4 % / Rmerge(I) obs: 1.084 / Mean I/σ(I) obs: 4.01 / Num. unique obs: 1851 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.12→30.98 Å / SU ML: 0.2209 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.374
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2183 965 5.1 %
Rwork0.1852 17949 -
obs0.1869 18916 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.16 Å2
Refinement stepCycle: LAST / Resolution: 2.12→30.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2214 0 70 123 2407
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00282307
X-RAY DIFFRACTIONf_angle_d0.46673087
X-RAY DIFFRACTIONf_chiral_restr0.0357353
X-RAY DIFFRACTIONf_plane_restr0.0038388
X-RAY DIFFRACTIONf_dihedral_angle_d11.1832889
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.12-2.230.28681560.22422497X-RAY DIFFRACTION99.96
2.23-2.370.24361380.20062486X-RAY DIFFRACTION100
2.37-2.550.25561320.20462512X-RAY DIFFRACTION99.96
2.55-2.810.23481290.18782549X-RAY DIFFRACTION100
2.81-3.220.22031410.19592538X-RAY DIFFRACTION99.96
3.22-4.050.20611330.16732598X-RAY DIFFRACTION99.96
4.05-30.980.19261360.17922769X-RAY DIFFRACTION99.86
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
17.08233845725-1.436547392150.3762469454053.83692419364-4.500649656676.719436519180.6756692375350.318610504913-0.324250075296-0.444810555738-0.01753817787371.371886236360.218260888851-0.971629393913-0.4102768909580.2092003751730.103290287796-0.08744971183550.678755162851-0.09476003935050.741327821003-14.53318.9027.61
20.5941600074050.6746360586560.1732735801655.93367087786-2.043151641991.050312601630.103039272389-0.2063787559060.06255065930850.752663389594-0.1633904498910.058580315224-0.424862775971-0.08998921437450.1131011823550.2974786880720.0275896493467-0.004540964049820.378502838278-0.06612459739330.2267440461218.31520.18620.634
35.61331124462-1.26066519084-0.477712224512.78421807631-1.878163330853.008858903630.264364921892-0.869609960065-0.496158107790.3370832929810.1662896663650.6148219599710.231414662071-0.4257886555-0.0470940159730.32205837959-0.1198222445320.1826031327140.6995281934140.04168410716030.569986196089-7.31-4.22731.083
41.23651087381-0.4327437001060.1471726433554.45105481548-2.140960216741.896801775960.0244334494566-0.0788431110493-0.0348115346047-0.06241869686870.04153607247650.4541125063880.0162577273565-0.393728045823-0.00916413402870.158784898360.0342674924204-0.0179515117560.348534182753-0.03078654163780.275929072038-1.3228.48514.554
54.506253390770.8037253867820.6847328661253.400460169380.07623749331383.05066344190.03815025664930.515653365986-0.0871852673438-0.432633558890.0480911734627-0.0339676117667-0.152278597870.191045478053-0.07770223150270.2123100880980.06878279171680.002729779108150.23832871637-0.02994465807210.1882026285299.51320.8294.629
65.004511318715.7997335232-1.09169863849.251203976090.2092343301264.9689089324-0.3031443699410.94202842526-0.593200594942-0.2241817661810.3686540347720.2356676066240.499873491744-0.57218793578-0.05472514309110.2721712767860.0504138315805-0.02794704206260.393155162154-0.05901027269640.3531051023252.3634.1884.747
75.66920774022-2.54998205430.4183065843151.62707855317-1.578032765154.06638364301-0.09586389088790.206120900879-0.787634834339-0.3319164561890.425042749510.8597078284510.67727984269-0.9003765292640.1825204241040.355268105496-0.157427994507-0.02240224625150.5554072270410.001791739543330.49698653807-9.312-4.1219.906
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN D AND RESID 2260:2271 )D2260 - 2271
2X-RAY DIFFRACTION2( CHAIN A AND RESID 202:251 )A202 - 251
3X-RAY DIFFRACTION3( CHAIN A AND RESID 252:276 )A252 - 276
4X-RAY DIFFRACTION4( CHAIN A AND RESID 277:377 )A277 - 377
5X-RAY DIFFRACTION5( CHAIN A AND RESID 378:430 )A378 - 430
6X-RAY DIFFRACTION6( CHAIN A AND RESID 431:458 )A431 - 458
7X-RAY DIFFRACTION7( CHAIN A AND RESID 459:477 )A459 - 477

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