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

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Basic information

Entry
Database: PDB / ID: 8fke
TitleCrystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and inverse agonist SR32904
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: 2.02 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 SR32904
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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,4315
Polymers34,0152
Non-polymers4163
Water4,342241
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1090 Å2
ΔGint-7 kcal/mol
Surface area14620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.888, 61.888, 164.288
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

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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.: 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 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
#3: Chemical ChemComp-Y5T / 2-chloro-N-(2-methylpyridin-4-yl)-5-nitrobenzamide


Mass: 291.690 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H10ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 241 / Source method: isolated from a natural source / Formula: H2O
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: 2.22 Å3/Da / Density % sol: 44.61 %
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: 0.979318 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 31, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979318 Å / Relative weight: 1
ReflectionResolution: 2.02→41.07 Å / Num. obs: 21902 / % possible obs: 99.66 % / Redundancy: 12.6 % / Biso Wilson estimate: 34.56 Å2 / Rmerge(I) obs: 0.07696 / Net I/σ(I): 23.01
Reflection shellResolution: 2.02→2.088 Å / Redundancy: 12 % / Rmerge(I) obs: 1.073 / Mean I/σ(I) obs: 2.28 / Num. unique obs: 2109 / % possible all: 97.86

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.02→41.07 Å / SU ML: 0.2674 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.4022
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2491 1083 4.95 %
Rwork0.1943 20799 -
obs0.197 21902 99.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 41.32 Å2
Refinement stepCycle: LAST / Resolution: 2.02→41.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2255 0 27 241 2523
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00232320
X-RAY DIFFRACTIONf_angle_d0.46253120
X-RAY DIFFRACTIONf_chiral_restr0.0362359
X-RAY DIFFRACTIONf_plane_restr0.0033396
X-RAY DIFFRACTIONf_dihedral_angle_d10.4794897
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.02-2.110.35141580.27412469X-RAY DIFFRACTION98.28
2.11-2.220.2871290.22372570X-RAY DIFFRACTION100
2.22-2.360.32431310.22742527X-RAY DIFFRACTION99.36
2.36-2.540.25071220.21752577X-RAY DIFFRACTION99.96
2.54-2.80.24361250.21452590X-RAY DIFFRACTION99.96
2.8-3.20.2641510.21482589X-RAY DIFFRACTION99.96
3.2-4.030.22651220.17632662X-RAY DIFFRACTION99.96
4.03-41.070.22341450.1682815X-RAY DIFFRACTION99.9
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)
10.6990869333891.06303936974-0.1335277793985.82014540652-2.458372499311.45057483014-0.0571229802183-0.160592260815-0.129690790930.293692787749-0.0349830638798-0.0479513570575-0.152344236409-0.1085918126240.009328622232420.2774240899730.04350296577690.01223266275630.342222176169-0.0370909916710.2622684860186.8236880792117.146608092122.2112712608
22.077115456830.5632248156230.1670771168944.61259744215-1.499812381652.985277376760.239056829307-0.3500896127490.04117211385280.488175304947-0.1126841736390.9925689352890.00693534096241-0.332265105071-0.2299943033580.2383840647040.03136658942040.03495171425490.415857198539-0.06710850762120.345447513735-9.0957593601311.782280215215.9703334875
30.9069471862650.239089716544-0.08473088522943.26157477087-1.016907984781.50419503512-0.0131333832013-0.000837202929979-0.1284235327-0.2591401708110.005146545431170.03558804933350.0329498851812-0.106972029620.007414111239970.2090814512080.0328035535803-0.00593354969580.233034011698-0.05674041056110.2070829870845.1091304166111.776567295811.0890423975
43.530362151752.15859028573-1.523708348422.5928669806-1.983254743852.77658455521-0.05873112403910.247910132391-0.361469665229-0.2683489788690.1784109490970.02543086628880.331128418962-0.350987404804-0.07296632032490.3218418629870.00931569192972-0.02066715284350.293486180313-0.07039747011010.383168559148-1.727086617850.040398851048111.6868516645
51.337830048281.62233210817-2.438419228354.092258767-4.048202054585.00419499882-0.02015359184581.17959059698-0.338187453585-0.6502971877320.5448426145651.775969414550.740853776179-0.858776299662-0.5061849986630.402089757980.0377411175349-0.127756099350.641791935908-0.1361397094720.694808767456-14.631985448317.99386679087.12992400912
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 202 through 257 )AA202 - 2571 - 56
22chain 'A' and (resid 258 through 310 )AA258 - 31057 - 101
33chain 'A' and (resid 311 through 430 )AA311 - 430102 - 221
44chain 'A' and (resid 431 through 477 )AA431 - 477222 - 268
55chain 'D' and (resid 2260 through 2272 )DE2260 - 22722 - 14

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