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- PDB-8sc9: Structure of PPARG in complex with MTX-531 -

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Basic information

Entry
Database: PDB / ID: 8sc9
TitleStructure of PPARG in complex with MTX-531
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION/INHIBITOR / TRANSCRIPTION / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


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 / positive regulation of cholesterol transport / negative regulation of cellular response to transforming growth factor beta stimulus / : / arachidonate 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 / 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 / response to lipid / negative regulation of SMAD protein signal transduction / negative regulation of type II interferon-mediated signaling pathway / LBD domain binding / 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 / 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 / intracellular receptor signaling pathway / positive regulation of adipose tissue development / hormone-mediated signaling pathway / peroxisome proliferator activated receptor signaling pathway / epithelial cell differentiation / regulation of cellular response to insulin stimulus / response to nutrient / negative regulation of miRNA transcription / peptide binding / negative regulation of angiogenesis / transcription coregulator binding / positive regulation of apoptotic signaling pathway / Regulation of PTEN gene transcription / fatty acid metabolic process / placenta development / SUMOylation of intracellular receptors / negative regulation of smooth muscle cell proliferation / negative regulation of transforming growth factor beta receptor signaling pathway / mRNA transcription by RNA polymerase II / PPARA activates gene expression / regulation of circadian rhythm / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / regulation of blood pressure / lipid metabolic process / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / nuclear receptor activity / rhythmic process / glucose homeostasis / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / double-stranded DNA binding / DNA-binding transcription factor binding / cellular response to hypoxia / sequence-specific DNA binding / nucleic acid binding / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / receptor complex / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / innate immune response / negative regulation of gene expression / negative regulation of DNA-templated transcription / intracellular membrane-bounded organelle / chromatin binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II
Similarity search - Function
Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / : / 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. ...Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / : / 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
: / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.855 Å
AuthorsWhitehead, C.E. / Leopold, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Cancer / Year: 2024
Title: A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.
Authors: Whitehead, C.E. / Ziemke, E.K. / Frankowski-McGregor, C.L. / Mumby, R.A. / Chung, J. / Li, J. / Osher, N. / Coker, O. / Baladandayuthapani, V. / Kopetz, S. / Sebolt-Leopold, J.S.
History
DepositionApr 5, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
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 / _pdbx_entry_details.has_protein_modification

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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
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,04814
Polymers63,4702
Non-polymers1,57812
Water4,594255
1
A: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3787
Polymers31,7351
Non-polymers6446
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6697
Polymers31,7351
Non-polymers9346
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)93.205, 61.383, 118.741
Angle α, β, γ (deg.)90, 102.52, 90
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 31734.863 Da / Num. of mol.: 2 / Fragment: UNP residues 232-505
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: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-TAM / TRIS(HYDROXYETHYL)AMINOMETHANE


Mass: 163.215 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H17NO3 / Comment: pH buffer*YM
#4: Chemical ChemComp-D0D / N-[(5P)-2-chloro-5-(4-{[(1R)-1-phenylethyl]amino}quinazolin-6-yl)pyridin-3-yl]methanesulfonamide


Mass: 453.945 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20ClN5O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.61 Å3/Da / Density % sol: 52.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 2.2 M Ammonium Sulfate, 0.1 M BIS-TRIS-Propane pH 9.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.000032 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 17, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000032 Å / Relative weight: 1
ReflectionResolution: 1.855→33.218 Å / Num. obs: 35249 / % possible obs: 63.4 % / Redundancy: 6.8 % / Biso Wilson estimate: 57.8 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.024 / Rrim(I) all: 0.063 / Net I/σ(I): 14.4
Reflection shellResolution: 1.855→2.172 Å / Rmerge(I) obs: 0.907 / Mean I/σ(I) obs: 2 / Num. unique obs: 3526 / CC1/2: 0.813 / Rpim(I) all: 0.373 / Rrim(I) all: 0.982 / % possible all: 17

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
XDSJan 10, 2022data reduction
Aimless0.7.9data scaling
STARANISO2.3.87data scaling
BUSTER2.11.8 (8-JUN-2022)phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.855→33.22 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.941 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.24 / SU Rfree Blow DPI: 0.187
RfactorNum. reflection% reflectionSelection details
Rfree0.2411 1762 -RANDOM
Rwork0.2116 ---
obs0.213 35249 63.4 %-
Displacement parametersBiso mean: 61.02 Å2
Baniso -1Baniso -2Baniso -3
1--1.8573 Å20 Å20.2425 Å2
2--2.619 Å20 Å2
3----0.7617 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: LAST / Resolution: 1.855→33.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4188 0 92 255 4535
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0058798HARMONIC8
X-RAY DIFFRACTIONt_angle_deg0.6716000HARMONIC8
X-RAY DIFFRACTIONt_dihedral_angle_d2668SINUSOIDAL12
X-RAY DIFFRACTIONt_gen_planes1338HARMONIC10
X-RAY DIFFRACTIONt_it4414HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion578SEMIHARMONIC5
X-RAY DIFFRACTIONt_utility_distance1HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact7828SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.9
X-RAY DIFFRACTIONt_other_torsion12.75
LS refinement shellResolution: 1.855→1.99 Å
RfactorNum. reflection% reflection
Rfree0.3191 39 -
Rwork0.2821 --
obs--6.83 %
Refinement TLS params.

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)
11.08350.6587-0.32730.5092-0.25561.4882-0.2124-0.0217-0.1892-0.02170.2030.1369-0.18920.13690.0094-0.06270.0974-0.00320.13080.0342-0.093612.8164-0.896317.0632
21.01190.04560.10370.1587-0.03292.01630.10760.0529-0.11690.05290.03060.2615-0.11690.2615-0.13810.02830.07730.06660.0030.036-0.051630.8887-22.51134.4714
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A204 - 476
2X-RAY DIFFRACTION1{ A|* }A1001 - 1011
3X-RAY DIFFRACTION2{ B|* }B207 - 476
4X-RAY DIFFRACTION2{ B|* }B1001 - 2001

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