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- PDB-8b8y: Crystal structure of PPARG and NCOR2 with an inverse agonist (com... -

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Basic information

Entry
Database: PDB / ID: 8b8y
TitleCrystal structure of PPARG and NCOR2 with an inverse agonist (compound 7e)
Components
  • Nuclear receptor corepressor 2
  • Peroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / nuclear hormone receptor transcription factor
Function / homology
Function and homology information


Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / regulation of cellular ketone metabolic process / nuclear glucocorticoid receptor binding / Notch binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / Notch-HLH transcription pathway / nuclear retinoid X receptor binding / Regulation of MECP2 expression and activity / estrous cycle ...Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / regulation of cellular ketone metabolic process / nuclear glucocorticoid receptor binding / Notch binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / Notch-HLH transcription pathway / nuclear retinoid X receptor binding / Regulation of MECP2 expression and activity / estrous cycle / Complex I biogenesis / Respiratory electron transport / mitochondrial ATP synthesis coupled electron transport / negative regulation of miRNA transcription / mitochondrial respiratory chain complex I assembly / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / : / transcription repressor complex / lactation / Regulation of lipid metabolism by PPARalpha / cerebellum development / SUMOylation of transcription cofactors / : / mitochondrial electron transport, NADH to ubiquinone / proton motive force-driven mitochondrial ATP synthesis / HDACs deacetylate histones / Mitochondrial protein degradation / NADH dehydrogenase (ubiquinone) activity / Downregulation of SMAD2/3:SMAD4 transcriptional activity / PPARA activates gene expression / HCMV Early Events / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / mitochondrial membrane / aerobic respiration / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / histone deacetylase binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / nuclear matrix / transcription corepressor activity / response to estradiol / nuclear body / mitochondrial inner membrane / negative regulation of DNA-templated transcription / chromatin binding / chromatin / negative regulation of transcription by RNA polymerase II / mitochondrion / DNA binding / nucleoplasm / membrane / nucleus
Similarity search - Function
N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / NADH dehydrogenase 1, beta subcomplex, subunit 6 ...N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / NADH dehydrogenase 1, beta subcomplex, subunit 6 / NADH:ubiquinone oxidoreductase, NDUFB6/B17 subunit / Homeobox-like domain superfamily
Similarity search - Domain/homology
Chem-Q33 / NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 / Nuclear receptor corepressor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsHolton, S.J. / Friberg, A. / Orsi, D.L. / Pook, E. / Siegel, S. / Lemke, C.T. / Stellfeld, T. / Puetter, V. / Goldstein, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists.
Authors: Orsi, D.L. / Ferrara, S.J. / Siegel, S. / Friberg, A. / Bouche, L. / Pook, E. / Lienau, P. / Bluck, J.P. / Lemke, C.T. / Akcay, G. / Stellfeld, T. / Meyer, H. / Putter, V. / Holton, S.J. / ...Authors: Orsi, D.L. / Ferrara, S.J. / Siegel, S. / Friberg, A. / Bouche, L. / Pook, E. / Lienau, P. / Bluck, J.P. / Lemke, C.T. / Akcay, G. / Stellfeld, T. / Meyer, H. / Putter, V. / Holton, S.J. / Korr, D. / Jerchel-Furau, I. / Pantelidou, C. / Strathdee, C.A. / Meyerson, M. / Eis, K. / Goldstein, J.T.
History
DepositionOct 5, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Peroxisome proliferator-activated receptor gamma
B: Peroxisome proliferator-activated receptor gamma
C: Nuclear receptor corepressor 2
D: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,8016
Polymers69,0024
Non-polymers7992
Water3,657203
1
A: Peroxisome proliferator-activated receptor gamma
C: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9003
Polymers34,5012
Non-polymers3991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1270 Å2
ΔGint-11 kcal/mol
Surface area13960 Å2
MethodPISA
2
B: Peroxisome proliferator-activated receptor gamma
D: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9003
Polymers34,5012
Non-polymers3991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-8 kcal/mol
Surface area13100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.558, 86.759, 120.475
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Peroxisome proliferator-activated receptor gamma / PPAR-gamma / Nuclear receptor subfamily 1 group C member 3


Mass: 31862.994 Da / Num. of mol.: 2
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 2 / N-CoR2 / CTG repeat protein 26 / SMAP270 / Silencing mediator of retinoic acid and thyroid hormone ...N-CoR2 / CTG repeat protein 26 / SMAP270 / Silencing mediator of retinoic acid and thyroid hormone receptor / SMRT / T3 receptor-associating factor / TRAC / Thyroid- / retinoic-acid-receptor-associated corepressor


Mass: 2638.073 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9Y618
#3: Chemical ChemComp-Q33 / 4,5-bis(chloranyl)-~{N}3-phenyl-~{N}1-(phenylmethyl)benzene-1,3-dicarboxamide


Mass: 399.270 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H16Cl2N2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / 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: 2.29 Å3/Da / Density % sol: 46.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 3350 20%, HCOOMg 0.2 M

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.9686 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2→120.47 Å / Num. obs: 43770 / % possible obs: 99.9 % / Redundancy: 13.5 % / CC1/2: 0.999 / Rrim(I) all: 0.112 / Net I/σ(I): 15.89
Reflection shellResolution: 2→2.12 Å / Redundancy: 13.8 % / Mean I/σ(I) obs: 1.23 / Num. unique obs: 6973 / CC1/2: 0.491 / Rrim(I) all: 2.174 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 2→60.31 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.944 / SU B: 5.123 / SU ML: 0.134 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.169 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2419 2178 5 %RANDOM
Rwork0.1934 ---
obs0.1958 41592 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 131.46 Å2 / Biso mean: 49.159 Å2 / Biso min: 27.88 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å2-0 Å20 Å2
2--0.05 Å2-0 Å2
3---0.01 Å2
Refinement stepCycle: final / Resolution: 2→60.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4132 0 52 203 4387
Biso mean--58.16 51.22 -
Num. residues----519
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134281
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164240
X-RAY DIFFRACTIONr_angle_refined_deg1.511.6535761
X-RAY DIFFRACTIONr_angle_other_deg1.3191.5829788
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4475520
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.96824.049205
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.15515829
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8241518
X-RAY DIFFRACTIONr_chiral_restr0.0750.2561
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024718
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02892
LS refinement shellResolution: 2→2.05 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.31 162 -
Rwork0.318 3001 -
obs--99.62 %

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