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

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Basic information

Entry
Database: PDB / ID: 8fkd
TitleCrystal structure of PPARgamma ligand-binding domain in complex with N-CoR peptide and inverse agonist SR33068
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 / retinoic acid receptor signaling pathway / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / 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 / negative regulation of signaling receptor activity / regulation of cellular response to insulin stimulus / cell maturation / 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: 2.22 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 SR33068
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)34,5046
Polymers34,0152
Non-polymers4894
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1070 Å2
ΔGint-8 kcal/mol
Surface area15090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.125, 62.125, 162.209
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-Y5O / 2-chloro-N-(6-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 / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 2.17 Å3/Da / Density % sol: 43.25 %
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: 2.22→42.4 Å / Num. obs: 16390 / % possible obs: 98.61 % / Redundancy: 12.4 % / Biso Wilson estimate: 37.58 Å2 / Rmerge(I) obs: 0.1217 / Net I/σ(I): 13.5
Reflection shellResolution: 2.22→2.302 Å / Redundancy: 10.5 % / Rmerge(I) obs: 1.479 / Mean I/σ(I) obs: 1.91 / Num. unique obs: 1571 / % possible all: 86.71

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.22→42.4 Å / SU ML: 0.341 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 29.6178
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2514 848 5.24 %
Rwork0.2166 15339 -
obs0.2183 16389 98.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 50.52 Å2
Refinement stepCycle: LAST / Resolution: 2.22→42.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2254 0 32 98 2384
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022319
X-RAY DIFFRACTIONf_angle_d0.44393115
X-RAY DIFFRACTIONf_chiral_restr0.0361358
X-RAY DIFFRACTIONf_plane_restr0.0039395
X-RAY DIFFRACTIONf_dihedral_angle_d13.0319895
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.22-2.360.40931270.38242305X-RAY DIFFRACTION91.98
2.36-2.540.25131380.26842536X-RAY DIFFRACTION100
2.54-2.80.32031450.25352551X-RAY DIFFRACTION99.89
2.8-3.20.27891390.25452557X-RAY DIFFRACTION99.96
3.2-4.040.23131540.19162602X-RAY DIFFRACTION99.89
4.04-42.40.21211450.17642788X-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)
12.191261226430.1112204185340.4565214323062.98181193586-0.9432008402934.15706107957-0.00248427930566-0.2043690749450.1595092338110.0295285699029-0.0839106128901-0.0419094390053-0.0863545531876-0.1171411020230.06834268290770.397696864820.02039443526160.006166769558920.331301171883-0.08550600503870.3057901364469.4141666411225.708953114415.3227545617
26.90018080450.4071827695452.090793953593.550049294233.244636403944.071330691980.160772895155-0.851517731944-0.6254159168281.17780470327-0.2400527513710.387852059067-0.390259556935-1.049090917470.0708503437260.6428249589710.09528390390490.01455542584330.5476670387640.1256944041390.2348632116462.500283291141.155214337333.9179915864
30.8461359360490.286186095259-0.4815519633165.33239457846-2.064467828172.28755403504-0.0713435562113-0.0323312411071-0.1085102279540.1523717052150.1704217810420.702019536634-0.0149932246408-0.497440588513-0.1182947400690.2739763204670.0296689038136-0.005857625855860.403222710318-0.02433239579950.415877595226-6.9878421977912.753650302212.6872433113
46.84248437013.110519985450.2371694483387.06151344719-3.231312410664.51174173596-0.00269430462258-0.0224870423341-0.0942548406743-0.0678218902208-0.000763642199848-0.05277389820720.178891909011-0.1007755399370.06266453600970.2747322566130.052593770637-0.009814588709350.3137296451610.0114129397990.2652866324674.22920339726-0.52538604471119.6840049541
57.368439609720.2667935228272.867146030582.83254984964-0.2863178672813.905294607420.1442538007280.364655844955-0.129069859306-0.264525669323-0.0610388438524-0.07068546125420.03928521552890.213820689621-0.08772102946340.3093853922760.04102355317670.01934962779690.257017314387-0.0497055889680.2153145023929.5448921175420.82616820034.53296519835
65.719206840992.48192903466-2.046233462812.49853715476-1.475377681832.99864932682-0.219161637680.386262545425-0.564079447917-0.1582759624760.189360321950.08737349387380.349545779255-0.4064723825820.02194619534060.3381456534420.0356858954843-0.009829591576690.299733059193-0.03718381109750.376379004911-1.99602446688-0.091759186003211.2334489528
71.887293865380.0644140491119-0.844565294419.25752764981-6.566896347127.31767058949-0.04530741442810.496598627044-0.198623596593-0.5862708972690.0597516887692.054255107140.682454159235-1.282087985740.09453486921140.438576782494-0.0457537361794-0.07808160169710.631075099619-0.1208471164860.713166095262-14.496776330917.53237032226.78755855035
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 237 )AA202 - 2371 - 36
22chain 'A' and (resid 238 through 258 )AA238 - 25837 - 57
33chain 'A' and (resid 259 through 333 )AA259 - 33358 - 124
44chain 'A' and (resid 334 through 377 )AA334 - 377125 - 168
55chain 'A' and (resid 378 through 430 )AA378 - 430169 - 221
66chain 'A' and (resid 431 through 477 )AA431 - 477222 - 268
77chain 'D' and (resid 2259 through 2272 )DF2259 - 22721 - 14

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