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

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Basic information

Entry
Database: PDB / ID: 8fkf
TitleCrystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and inverse agonist SR36706
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 / MECP2 regulates transcription factors / negative regulation of glycolytic process ...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 / MECP2 regulates transcription factors / negative regulation of glycolytic process / 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 / nuclear thyroid hormone receptor binding / positive regulation of low-density lipoprotein receptor activity / positive regulation of adiponectin secretion / lipoprotein transport / negative regulation of sequestering of triglyceride / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / DNA binding domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / Notch-HLH transcription pathway / negative regulation of fatty acid metabolic process / 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 / histone deacetylase complex / negative regulation of macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / negative regulation of lipid storage / negative regulation of blood vessel endothelial cell migration / Regulation of MECP2 expression and activity / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / positive regulation of cholesterol efflux / spindle assembly / positive regulation of fat cell differentiation / retinoic acid receptor signaling pathway / negative regulation of osteoblast differentiation / positive regulation of DNA binding / cell fate commitment / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Nuclear signaling by ERBB4 / negative regulation of signaling receptor activity / cell maturation / regulation of cellular response to insulin stimulus / 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 / fatty acid metabolic process / negative regulation of miRNA transcription / placenta development / negative regulation of MAP kinase activity / Regulation of PTEN gene transcription / transcription coregulator binding / HDACs deacetylate histones / nuclear receptor binding / negative regulation of smooth muscle cell proliferation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / peptide binding / negative regulation of transforming growth factor beta receptor signaling pathway / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / 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 / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / 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: 1.82 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 SR36706
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)34,6518
Polymers34,0152
Non-polymers6366
Water3,945219
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1820 Å2
ΔGint-2 kcal/mol
Surface area14040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.765, 61.765, 161.084
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-687-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AD

#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

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Non-polymers , 4 types, 225 molecules

#3: Chemical ChemComp-Y5X / 2-chloro-N-(5-fluoropyridin-3-yl)-5-nitrobenzamide


Mass: 295.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H7ClFN3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 219 / 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: 2.18 Å3/Da / Density % sol: 43.6 %
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: Aug 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.82→42.15 Å / Num. obs: 28621 / % possible obs: 99.83 % / Redundancy: 25.1 % / Biso Wilson estimate: 27.75 Å2 / Rmerge(I) obs: 0.05594 / Net I/σ(I): 39.82
Reflection shellResolution: 1.82→1.89 Å / Redundancy: 26.2 % / Rmerge(I) obs: 0.4607 / Mean I/σ(I) obs: 6.35 / Num. unique obs: 2792 / % possible all: 99.64

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.82→42.15 Å / SU ML: 0.226 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.9813
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2164 1354 4.73 %
Rwork0.1808 27264 -
obs0.1825 28620 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 34.11 Å2
Refinement stepCycle: LAST / Resolution: 1.82→42.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2211 0 41 219 2471
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01032290
X-RAY DIFFRACTIONf_angle_d1.0333078
X-RAY DIFFRACTIONf_chiral_restr0.0605355
X-RAY DIFFRACTIONf_plane_restr0.0075390
X-RAY DIFFRACTIONf_dihedral_angle_d12.5807885
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.82-1.890.36921340.30712657X-RAY DIFFRACTION99.64
1.89-1.970.22711260.22482665X-RAY DIFFRACTION99.89
1.97-2.060.18971300.17412676X-RAY DIFFRACTION99.75
2.06-2.160.2181400.1752678X-RAY DIFFRACTION99.93
2.16-2.30.23081580.18432682X-RAY DIFFRACTION100
2.3-2.480.22061170.17732717X-RAY DIFFRACTION99.75
2.48-2.730.20141320.17442707X-RAY DIFFRACTION99.89
2.73-3.120.21661270.19152756X-RAY DIFFRACTION100
3.12-3.930.21511460.16512771X-RAY DIFFRACTION99.97
3.93-42.150.20471440.17492955X-RAY DIFFRACTION99.61
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)
18.112837701276.42748999227-4.590650298857.04298970309-4.787545083327.73681257092-0.0269081482673-0.158070281710.335143682304-0.0563037573683-0.0589847436401-0.0278810023983-0.3807131612990.1630531075540.04057091285770.2055943262010.0487040743167-0.04156981636180.160388327741-0.05172685647060.16730602099110.836031288330.70640600110.8484368495
20.04959591520170.345362134165-0.1979066368433.63564182133-2.183811344611.30237779909-0.010805382953-0.20279183662-0.04427908855031.052408625810.2011148969630.0812112043126-0.590088914373-0.343066029468-0.2208091351220.4464205156640.02021364022980.03078208130270.3139427187390.009952130841020.2146391728745.401277588669.6899740200429.2563240505
36.60893992639-1.388067572892.881381497996.02495152929-2.359575747075.246023618260.0487990821433-1.37039836977-0.2178794511720.3288007424020.1058623543690.632419126928-0.126374367387-0.866215182167-0.2919895752520.309280504951-0.02901571040450.1293802837970.5736578851510.0985889456890.415609578907-5.99988362961-4.1669367712532.1144343331
40.675583938346-0.4857096846450.2352709229322.81665190829-1.464983402031.653609137770.00409065879795-0.118183743945-0.0957916561667-0.02651114745840.07947937733970.4314568746060.0495161559249-0.306340428096-0.06478798915890.1129439742950.00944186750715-0.011066026160.229438480984-0.00981925559130.212152104338-3.094136104688.9285745055614.1516545769
51.565070468260.665405513649-0.2662921023072.56234718558-0.002106219961711.198433234810.02303839983750.111566944355-0.0408311611757-0.205948564476-0.0687840587775-0.0736077754869-0.0346623214941-0.03731649724630.02881545465280.1142519943240.03220909846830.002340680558570.154535352196-0.0311894479170.08450778824919.6034074851217.30758096846.39574060773
61.904453582610.797161338378-1.470655271111.58614426535-0.9324569941373.09221872024-0.2351080948860.141472547318-0.496362954827-0.1847127807410.08400153496520.09454936479570.465649326486-0.5311432266430.1150617509410.232693293695-0.04170670531620.01330846774620.297549654621-0.02167423966960.327124241128-1.87267092195-0.1456761240510.9878008261
77.315466816042.13230802396-1.100496910085.44285076473-6.31658940167.9389960110.2749969124650.525523212328-0.400725826236-0.7679989771890.001631042314121.449146194750.440023807323-1.00153274056-0.3606709946870.2267438146340.0386630238162-0.09951501092170.478555336547-0.1225025189130.521005489782-14.329658383617.93675467576.56133174072
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 251 )AA226 - 25125 - 50
33chain 'A' and (resid 252 through 276 )AA252 - 27651 - 62
44chain 'A' and (resid 277 through 364 )AA277 - 36463 - 150
55chain 'A' and (resid 365 through 430 )AA365 - 430151 - 216
66chain 'A' and (resid 431 through 477 )AA431 - 477217 - 263
77chain 'D' and (resid 2260 through 2272 )DH2260 - 22722 - 14

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