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

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Basic information

Entry
Database: PDB / ID: 8fkc
TitleCrystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and inverse agonist SR33544
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


: / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of glycolytic process / nuclear thyroid hormone receptor binding / prostaglandin receptor activity / : / negative regulation of receptor signaling pathway via STAT / MECP2 regulates transcription factors / negative regulation of vascular endothelial cell proliferation ...: / Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / negative regulation of glycolytic process / nuclear thyroid hormone receptor 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 / negative regulation of JNK cascade / 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 / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of vascular associated smooth muscle cell apoptotic process / negative regulation of fatty acid metabolic process / WW domain binding / positive regulation of fatty acid metabolic process / STAT family protein binding / response to lipid / Notch-HLH transcription pathway / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / negative regulation of cholesterol storage / locomotor rhythm / negative regulation of SMAD protein signal transduction / lipid homeostasis / E-box binding / alpha-actinin binding / R-SMAD binding / histone deacetylase complex / negative regulation of vascular associated smooth muscle cell proliferation / monocyte differentiation / negative regulation of blood vessel endothelial cell migration / white fat cell differentiation / negative regulation of macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / Regulation of MECP2 expression and activity / negative regulation of lipid storage / negative regulation of BMP signaling pathway / positive regulation of cholesterol efflux / cell fate commitment / negative regulation of osteoblast differentiation / negative regulation of mitochondrial fission / positive regulation of fat cell differentiation / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Nuclear signaling by ERBB4 / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / retinoic acid receptor signaling pathway / cell maturation / spindle assembly / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / negative regulation of MAPK cascade / intracellular receptor signaling pathway / hormone-mediated signaling pathway / positive regulation of adipose tissue development / Regulation of lipid metabolism by PPARalpha / transcription repressor complex / peroxisome proliferator activated receptor signaling pathway / response to nutrient / epithelial cell differentiation / regulation of cellular response to insulin stimulus / peptide binding / negative regulation of miRNA transcription / negative regulation of angiogenesis / placenta development / nuclear receptor binding / Regulation of PTEN gene transcription / positive regulation of apoptotic signaling pathway / transcription coregulator binding / HDACs deacetylate histones / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / mRNA transcription by RNA polymerase II / Heme signaling / negative regulation of transforming growth factor beta receptor signaling pathway / fatty acid metabolic process / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / regulation of circadian rhythm / Nuclear Receptor transcription pathway / NOTCH1 Intracellular Domain Regulates Transcription / Transcriptional regulation of white adipocyte differentiation / lipid metabolic process / positive regulation of miRNA transcription / regulation of blood pressure / negative regulation of inflammatory response / DNA-binding transcription repressor activity, RNA polymerase II-specific / Constitutive Signaling by NOTCH1 PEST Domain Mutants
Similarity search - Function
N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Myb domain / SANT domain / Myb-like DNA-binding domain ...N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Myb domain / SANT 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 / 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
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: 1.42 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: Nat Commun / Year: 2025
Title: Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states.
Authors: MacTavish, B.S. / Zhu, D. / Shang, J. / Shao, Q. / He, Y. / Yang, Z.J. / Kamenecka, T.M. / Kojetin, D.J.
History
DepositionDec 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.2Apr 30, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)34,3804
Polymers34,0152
Non-polymers3652
Water4,846269
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1160 Å2
ΔGint-8 kcal/mol
Surface area14000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.054, 62.054, 160.719
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-720-

HOH

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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-Y5F / 2-chloro-N-(5-cyanopyridin-3-yl)-5-nitrobenzamide


Mass: 302.673 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H7ClN4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 269 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.19 Å3/Da / Density % sol: 43.93 %
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: Aug 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979318 Å / Relative weight: 1
ReflectionResolution: 1.42→43.88 Å / Num. obs: 60517 / % possible obs: 99.87 % / Redundancy: 25.5 % / Biso Wilson estimate: 21.9 Å2 / Rmerge(I) obs: 0.03887 / Net I/σ(I): 44.98
Reflection shellResolution: 1.42→1.468 Å / Redundancy: 20.8 % / Rmerge(I) obs: 1.065 / Mean I/σ(I) obs: 2.64 / Num. unique obs: 5857 / % possible all: 98.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.42→43.88 Å / SU ML: 0.1729 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.6271
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1975 3048 5.04 %
Rwork0.1853 57467 -
obs0.1859 60515 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.93 Å2
Refinement stepCycle: LAST / Resolution: 1.42→43.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2180 0 24 269 2473
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01132251
X-RAY DIFFRACTIONf_angle_d1.17483036
X-RAY DIFFRACTIONf_chiral_restr0.0864352
X-RAY DIFFRACTIONf_plane_restr0.0114386
X-RAY DIFFRACTIONf_dihedral_angle_d13.3096871
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.42-1.440.3341580.31452480X-RAY DIFFRACTION97.6
1.44-1.460.31331270.26452574X-RAY DIFFRACTION100
1.46-1.490.24091310.2182566X-RAY DIFFRACTION100
1.49-1.520.22051360.19512593X-RAY DIFFRACTION100
1.52-1.540.21891310.18462553X-RAY DIFFRACTION100
1.54-1.580.20781290.18272581X-RAY DIFFRACTION100
1.58-1.610.18091400.17822576X-RAY DIFFRACTION100
1.61-1.650.20961330.19642577X-RAY DIFFRACTION100
1.65-1.690.2171350.20062605X-RAY DIFFRACTION100
1.69-1.730.28151330.24672563X-RAY DIFFRACTION100
1.73-1.790.25891480.23232583X-RAY DIFFRACTION100
1.79-1.840.22631420.19822581X-RAY DIFFRACTION100
1.84-1.910.1991240.18422627X-RAY DIFFRACTION100
1.91-1.990.21981100.17732640X-RAY DIFFRACTION100
1.99-2.080.19081280.18162607X-RAY DIFFRACTION100
2.08-2.190.20351580.18932599X-RAY DIFFRACTION100
2.19-2.320.18681610.16882599X-RAY DIFFRACTION100
2.32-2.50.18111470.17422635X-RAY DIFFRACTION100
2.5-2.750.19581660.17782626X-RAY DIFFRACTION100
2.75-3.150.21011460.1892677X-RAY DIFFRACTION100
3.15-3.970.17421300.16732724X-RAY DIFFRACTION100
3.97-43.880.1791350.18872901X-RAY DIFFRACTION99.67
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)
17.928421628074.3138097494-1.768669514645.39314389297-2.306566103294.8680595751-0.0764483151599-0.06889675604370.485588325113-0.114921182245-0.04418106925480.00141400721851-0.3298298537190.1093967313760.0872586083450.2103000803350.0377392374372-0.03063040638150.167966563045-0.05749150050090.19844564019711.100478519630.781748895210.8703223894
21.83784724585-0.9700961791531.028884964163.6884688512-1.811613164826.3644744592-0.280920008933-0.373493039595-0.1127890335381.03740627562-0.0720706920674-0.1217691951450.648241826613-0.3195643432820.1306445492830.510834571496-0.01923126518370.0461925146730.272308704489-0.03590550902920.2138848217126.8993927864613.586474695128.4663068031
31.16483460237-0.5622527887010.4750256338842.56822918902-1.086918298481.277972823340.026155299824-0.144480813228-0.1037118872840.06353097525570.1230447229310.409964937919-0.00499733560128-0.320298913803-0.1363221626830.1271988949550.005961357241050.008388953492940.24529655249-0.01420927209470.215126835304-5.1220398085410.961690247614.3357592878
44.047354467052.3422602282-0.1752380940424.88939756159-2.17754091332.82694868201-0.0568975150255-0.177251890178-0.116225203115-0.05634495201520.03977268145370.07858116778310.151624596015-0.211160439020.0698978781990.1512948630450.009289707981830.007210760456730.18022409451-0.002556664192030.1673619509754.10915245594-0.4938576554119.3486194744
54.19984979970.2912796223351.729000391921.784352664620.2743661237582.636595415690.07362558227570.314258176656-0.0102714685589-0.166666578911-0.0271044920011-0.0687424769875-0.06602726881180.103544959361-0.04704453950190.174300663030.02769471827910.02040231898660.173142555666-0.02096351808910.1416268061219.7448314410220.87157525544.61265393573
61.090665910540.435619821049-0.3511900942091.2453724041-0.2163463998420.940509115061-0.1159163393760.0925476387795-0.349108199012-0.08459770507810.07302658383040.1601981739060.264068919058-0.2995472530630.009553024161530.207947452223-0.0419025574070.01248547078980.2412847618-0.01234422551170.282617778264-1.793747795650.00012149657468810.8591280444
78.546322768840.7723405521240.4662885193875.54558319559-0.9015511395258.191091600720.4788681406390.541096523108-0.335989281637-0.274532232183-0.1469587088611.454661680450.433253992126-0.761637836789-0.2369071621640.2072509506650.0509189568832-0.03138931984520.432242636816-0.06497609492740.470290038754-14.460295861618.31777869666.73796537972
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 225 )AA202 - 2251 - 24
22chain 'A' and (resid 226 through 246 )AA226 - 24625 - 45
33chain 'A' and (resid 247 through 333 )AA247 - 33346 - 116
44chain 'A' and (resid 334 through 377 )AA334 - 377117 - 160
55chain 'A' and (resid 378 through 430 )AA378 - 430161 - 213
66chain 'A' and (resid 431 through 477 )AA431 - 477214 - 260
77chain 'D' and (resid 2260 through 2272 )DD2260 - 22721 - 13

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