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

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Basic information

Entry
Database: PDB / ID: 8aqm
TitleCrystal structure of PPARG and NCOR2 with an inverse agonist (compound 6a)
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 / nuclear glucocorticoid receptor binding / negative regulation of androgen receptor signaling pathway / regulation of ketone metabolic process / 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 / Notch binding ...Loss of MECP2 binding ability to the NCoR/SMRT complex / nuclear glucocorticoid receptor binding / negative regulation of androgen receptor signaling pathway / regulation of ketone metabolic process / 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 / Notch binding / negative regulation of connective tissue replacement involved in inflammatory response wound healing / 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 / positive regulation of vascular associated smooth muscle cell apoptotic process / WW domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / response to lipid / negative regulation of SMAD protein signal transduction / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / Notch-HLH transcription pathway / negative regulation of cholesterol storage / lipid homeostasis / E-box binding / alpha-actinin binding / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of blood vessel endothelial cell migration / white fat cell differentiation / negative regulation of macrophage derived foam cell differentiation / Regulation of MECP2 expression and activity / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / negative regulation of BMP signaling pathway / positive regulation of cholesterol efflux / negative regulation of mitochondrial fission / cell fate commitment / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / negative regulation of MAPK cascade / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / retinoic acid receptor signaling pathway / cell maturation / estrous cycle / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / intracellular receptor signaling pathway / positive regulation of adipose tissue development / hormone-mediated signaling pathway / lactation / Regulation of lipid metabolism by PPARalpha / transcription repressor complex / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / response to nutrient / cerebellum development / negative regulation of miRNA transcription / peptide binding / SUMOylation of transcription cofactors / enzyme activator activity / negative regulation of angiogenesis / transcription coregulator binding / positive regulation of apoptotic signaling pathway / Regulation of PTEN gene transcription / fatty acid metabolic process / HDACs deacetylate histones / placenta development / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / Downregulation of SMAD2/3:SMAD4 transcriptional activity / mRNA transcription by RNA polymerase II / PPARA activates gene expression / regulation of circadian rhythm / Cytoprotection by HMOX1 / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / regulation of blood pressure / NOTCH1 Intracellular Domain Regulates Transcription / lipid metabolic process / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / RNA polymerase II transcription regulator complex / nuclear matrix
Similarity search - Function
N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / SANT domain profile. / Myb domain / SANT domain / Myb-like DNA-binding domain ...N-CoR, GPS2-interacting domain / : / G-protein pathway suppressor 2-interacting domain / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / SANT domain profile. / 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
Chem-O2O / Peroxisome proliferator-activated receptor gamma / Nuclear receptor corepressor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsFriberg, A. / Orsi, D.L. / Pook, E. / Braeuer, N. / Lemke, C.T. / Stellfeld, T. / Puetter, V. / Goldstein, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery and Structure-Based Design of Potent Covalent PPAR gamma Inverse-Agonists BAY-4931 and BAY-0069 .
Authors: Orsi, D.L. / Pook, E. / Brauer, N. / Friberg, A. / Lienau, P. / Lemke, C.T. / Stellfeld, T. / Bruggemeier, U. / Putter, V. / Meyer, H. / Baco, M. / Tang, S. / Cherniack, A.D. / Westlake, L. ...Authors: Orsi, D.L. / Pook, E. / Brauer, N. / Friberg, A. / Lienau, P. / Lemke, C.T. / Stellfeld, T. / Bruggemeier, U. / Putter, V. / Meyer, H. / Baco, M. / Tang, S. / Cherniack, A.D. / Westlake, L. / Bender, S.A. / Kocak, M. / Strathdee, C.A. / Meyerson, M. / Eis, K. / Goldstein, J.T.
History
DepositionAug 12, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Dec 28, 2022Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.3May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)69,8186
Polymers69,0024
Non-polymers8162
Water3,459192
1
A: Peroxisome proliferator-activated receptor gamma
C: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9093
Polymers34,5012
Non-polymers4081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-8 kcal/mol
Surface area13460 Å2
MethodPISA
2
B: Peroxisome proliferator-activated receptor gamma
D: Nuclear receptor corepressor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9093
Polymers34,5012
Non-polymers4081
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1120 Å2
ΔGint-10 kcal/mol
Surface area13610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.060, 94.530, 114.840
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-O2O / 2-chloranyl-~{N}-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]-5-nitro-benzamide


Mass: 407.807 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H14ClN3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 192 / 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: 2.4 Å3/Da / Density % sol: 48.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1M MES pH 6, 0.2M NH4Cl, 20% PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9799 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9799 Å / Relative weight: 1
ReflectionResolution: 2.3→49.08 Å / Num. obs: 30160 / % possible obs: 99.6 % / Redundancy: 6.7 % / Rsym value: 0.0733 / Net I/σ(I): 15.9
Reflection shellResolution: 2.3→2.44 Å / Mean I/σ(I) obs: 2.41 / Num. unique obs: 2000 / Rsym value: 0.703 / % possible all: 97.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 2.3→49.08 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.926 / SU B: 7.033 / SU ML: 0.165 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.294 / ESU R Free: 0.234 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2512 1508 5 %RANDOM
Rwork0.1919 ---
obs0.1948 28651 99.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 151.69 Å2 / Biso mean: 49.732 Å2 / Biso min: 18.26 Å2
Baniso -1Baniso -2Baniso -3
1-0.81 Å20 Å20 Å2
2---1.1 Å20 Å2
3---0.28 Å2
Refinement stepCycle: final / Resolution: 2.3→49.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4273 0 56 192 4521
Biso mean--44.95 46.93 -
Num. residues----534
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0144404
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174221
X-RAY DIFFRACTIONr_angle_refined_deg1.3941.6665924
X-RAY DIFFRACTIONr_angle_other_deg0.9351.6439859
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8895526
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.32723.865207
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.31415850
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9581518
X-RAY DIFFRACTIONr_chiral_restr0.0690.2572
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024755
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02775
LS refinement shellResolution: 2.3→2.358 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.447 103 -
Rwork0.362 1967 -
obs--94.74 %

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