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- PDB-4xta: MECHANISMS OF PPARgamma ACTIVATION BY NON-STEROIDAL ANTI-INFLAMMA... -

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Basic information

Entry
Database: PDB / ID: 4xta
TitleMECHANISMS OF PPARgamma ACTIVATION BY NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION / Nuclear receptor / transcription factor
Function / homology
Function and homology information


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 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 ...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 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 / positive regulation of low-density lipoprotein receptor activity / positive regulation of adiponectin secretion / lipoprotein transport / negative regulation of sequestering of triglyceride / DNA binding domain binding / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / 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 / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of macrophage derived foam cell differentiation / negative regulation of blood vessel endothelial cell migration / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / positive regulation of cholesterol efflux / 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 / regulation of cellular response to insulin stimulus / cell maturation / negative regulation of signaling receptor activity / epithelial cell differentiation / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / hormone-mediated signaling pathway / negative regulation of angiogenesis / response to nutrient / negative regulation of miRNA transcription / negative regulation of MAP kinase activity / fatty acid metabolic process / Regulation of PTEN gene transcription / transcription coregulator binding / negative regulation of smooth muscle cell proliferation / peptide binding / negative regulation of transforming growth factor beta receptor signaling pathway / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / placenta development / regulation of circadian rhythm / lipid metabolic process / PPARA activates gene expression / regulation of blood pressure / positive regulation of DNA-binding transcription factor activity / DNA-binding transcription repressor activity, RNA polymerase II-specific / positive regulation of miRNA transcription / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / cellular response to insulin stimulus / nuclear receptor activity / activation of cysteine-type endopeptidase activity involved in apoptotic process / : / rhythmic process / glucose homeostasis / cellular response to hypoxia / double-stranded DNA binding / DNA-binding transcription activator activity, RNA polymerase II-specific / DNA-binding transcription factor binding / sequence-specific DNA binding / nucleic acid binding / cell differentiation / receptor complex / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / intracellular membrane-bounded organelle / innate immune response / negative regulation of DNA-templated transcription / chromatin binding
Similarity search - Function
Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) ...Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Retinoid X Receptor / Retinoid X Receptor / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
2-[2,6-DICHLOROPHENYL)AMINO]BENZENEACETIC ACID / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 Å
AuthorsPuhl, A.C. / Webb, P. / Polikarpov, I.
CitationJournal: Nucl Recept Signal / Year: 2015
Title: Mechanisms of peroxisome proliferator activated receptor gamma regulation by non-steroidal anti-inflammatory drugs.
Authors: Puhl, A.C. / Milton, F.A. / Cvoro, A. / Sieglaff, D.H. / Campos, J.C. / Bernardes, A. / Filgueira, C.S. / Lindemann, J.L. / Deng, T. / Neves, F.A. / Polikarpov, I. / Webb, P.
History
DepositionJan 23, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_prerelease_seq / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)64,0624
Polymers63,4702
Non-polymers5922
Water70339
1
A: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0312
Polymers31,7351
Non-polymers2961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0312
Polymers31,7351
Non-polymers2961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: Peroxisome proliferator-activated receptor gamma
hetero molecules

B: Peroxisome proliferator-activated receptor gamma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0624
Polymers63,4702
Non-polymers5922
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555x+1/2,y+1/2,z1
Buried area2900 Å2
ΔGint-30 kcal/mol
Surface area23400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.400, 62.120, 117.180
Angle α, β, γ (deg.)90.000, 101.020, 90.000
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-DIF / 2-[2,6-DICHLOROPHENYL)AMINO]BENZENEACETIC ACID / DICLOFENAC


Mass: 296.149 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H11Cl2NO2 / Comment: antiinflammatory, medication*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / Source method: isolated from a natural source / Formula: H2O

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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: 2.6 Å3/Da / Density % sol: 52.7 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 1 M sodium citrate, 0.1 M HEPES pH 7.5, and 10 mM MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: LNLS / Beamline: W01B-MX2 / Wavelength: 1.4586 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Mar 25, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.4586 Å / Relative weight: 1
ReflectionResolution: 2.5→45.24 Å / Num. all: 21967 / Num. obs: 21967 / % possible obs: 96.8 % / Redundancy: 3 % / Biso Wilson estimate: 60.58 Å2 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.038 / Rrim(I) all: 0.069 / Rsym value: 0.057 / Net I/σ(I): 11 / Num. measured all: 65322
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym value% possible all
2.5-2.6430.4962928031110.0240.03394.8
7.91-45.242.80.03326.318016520.030.04286.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
PHASERphasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→45.04 Å / SU ML: 0.37 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.22 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.274 1133 5.16 %random
Rwork0.2121 20812 --
obs0.2153 21945 96.36 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 245.24 Å2 / Biso mean: 89.1402 Å2 / Biso min: 35.92 Å2
Refinement stepCycle: final / Resolution: 2.5→45.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3580 0 38 39 3657
Biso mean--95.53 69.66 -
Num. residues----491
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073678
X-RAY DIFFRACTIONf_angle_d0.9935008
X-RAY DIFFRACTIONf_chiral_restr0.033615
X-RAY DIFFRACTIONf_plane_restr0.004639
X-RAY DIFFRACTIONf_dihedral_angle_d12.8631260
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5001-2.61380.33051400.27552488262894
2.6138-2.75160.33341550.25082538269395
2.7516-2.9240.36171280.25282595272396
2.924-3.14970.31491550.24752574272997
3.1497-3.46660.28861340.22492649278397
3.4666-3.96790.25411440.19382634277898
3.9679-4.99810.23571400.1812673281398
4.9981-45.04740.26691370.21522661279895
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)
10.9863-1.3574-0.98344.04572.95018.2761-0.33510.1511-0.38040.25860.2378-0.015-0.18210.7452-0.00720.6014-0.22440.10311.2252-0.16760.6611-1.7973-3.2542-10.3042
22.21830.7907-1.6190.8001-0.80893.0632-0.00910.62880.29470.13620.21730.1009-1.5958-0.8804-0.09440.99940.2442-0.0291.13830.10340.5304-15.417310.434-10.0964
30.47270.13720.67312.27150.04081.2382-0.44821.2895-0.058-0.73210.32160.1611-0.1618-1.8710.08270.7013-0.207-0.11561.529-0.14010.5579-10.07840.9016-26.6066
45.8737-3.7679-2.11826.0917-0.81042.095-0.01290.45710.03720.60460.16610.1122-1.381-1.02640.06020.9007-0.07790.14271.0598-0.09640.5429-15.10832.7588-3.7986
51.3811-1.6551.45215.8229-1.34991.56660.16141.5795-0.7497-0.1774-0.43131.2827-0.3123-2.71940.30030.77560.3301-0.00912.1803-0.09540.5875-26.02585.5666-5.353
66.3184-1.4944-4.21113.46895.04798.7335-0.64580.9669-0.9635-0.5375-0.23251.5886-0.3787-2.4430.95470.7138-0.18760.04231.4551-0.32880.7646-20.0134-7.0881-10.6449
71.8434-1.04810.33455.9899-1.80147.7935-0.21250.7735-0.4736-0.61890.38760.3640.4221-0.6889-0.07340.5135-0.36950.07721.2668-0.22430.7003-7.0085-11.1776-24.4985
83.3347-3.13482.50696.2676-4.95556.7265-0.03960.0082-0.9981-0.99260.58142.14830.0911-2.4592-0.51960.6286-0.1834-0.09281.6423-0.09310.7872-22.4088-3.5107-21.2533
97.6231.7558-1.59595.1922-3.61572.50120.33760.45461.6233-0.56080.4307-0.23331.9579-0.0351-0.73951.26310.5331-0.00721.9554-0.12140.9061-20.422915.3006-24.2172
106.4686-1.03730.36986.5326-3.82396.801-0.9824-0.9924-1.25480.0118-0.1946-0.39611.51321.51630.30381.15340.06480.2377-0.1052-0.06450.988-21.0364-36.707-29.3686
117.1054-5.39244.56475.9928-3.01443.04980.48271.54-0.04-0.55430.35070.3761.5309-0.45170.31170.8279-0.1515-0.03310.7104-0.18590.6031-27.6923-28.5888-44.0246
120.85850.00080.75160.5499-1.06113.2930.30060.9952-0.1562-0.5364-0.0584-0.5658-0.6831-1.4855-0.02081.43740.73460.06052.72380.2558-0.0022-37.6889-19.6114-54.701
132.4038-1.2194-0.462.3921-0.25432.40060.46990.5342-0.2729-0.7043-0.136-0.03730.5271-1.7612-0.07890.67460.05210.08450.8685-0.00630.682-39.0597-24.3056-33.5232
146.7778-0.5251-2.33381.79650.02032.52380.13550.3627-0.2776-0.28850.10310.0224-0.025-0.3497-0.17280.6358-0.09330.05050.2997-0.03330.5155-32.1457-23.8519-29.8975
156.3897-1.8996-1.33971.53630.26663.64980.63512.5311.2554-0.6071-0.2985-0.0422-2.4714-1.5705-0.45981.4890.39190.1541.24780.35740.8111-36.6057-9.7576-45.6424
164.94260.4605-3.11820.8957-0.33158.30080.25540.16490.4352-0.07780.02890.0445-0.9420.0506-0.37790.696-0.15540.130.4242-0.09710.6218-24.4128-20.557-30.3571
177.0284-1.8447-5.10635.10372.56963.99480.3901-1.55290.1644-0.2091-0.1458-0.8899-0.94922.4184-0.46780.5105-0.06710.04140.6416-0.04970.6461-15.06-27.0917-24.5924
186.3465-4.6204-2.06823.54350.73316.75410.4562-0.42660.9602-0.49780.2075-0.0614-1.4649-0.3644-0.7060.80740.01670.08010.37190.0220.7784-27.2531-12.6057-29.4786
192.4627-0.2381.67172.5425-1.8662.65590.73870.11180.0915-1.4437-0.98110.4133-1.3333-1.18730.27861.01960.4018-0.03711.3817-0.05630.7693-51.2582-15.5113-31.0941
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 208 through 246 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 247 through 302 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 303 through 333 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 334 through 345 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 346 through 364 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 365 through 377 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 378 through 430 )A0
8X-RAY DIFFRACTION8chain 'A' and (resid 431 through 459 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 460 through 473 )A0
10X-RAY DIFFRACTION10chain 'B' and (resid 208 through 225 )B0
11X-RAY DIFFRACTION11chain 'B' and (resid 226 through 237 )B0
12X-RAY DIFFRACTION12chain 'B' and (resid 238 through 277 )B0
13X-RAY DIFFRACTION13chain 'B' and (resid 278 through 302 )B0
14X-RAY DIFFRACTION14chain 'B' and (resid 303 through 345 )B0
15X-RAY DIFFRACTION15chain 'B' and (resid 346 through 364 )B0
16X-RAY DIFFRACTION16chain 'B' and (resid 365 through 402 )B0
17X-RAY DIFFRACTION17chain 'B' and (resid 403 through 430 )B0
18X-RAY DIFFRACTION18chain 'B' and (resid 431 through 457 )B0
19X-RAY DIFFRACTION19chain 'B' and (resid 458 through 475 )B0

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