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- PDB-4l98: Crystal structure of the complex of F360L PPARgamma mutant with t... -

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Basic information

Entry
Database: PDB / ID: 4l98
TitleCrystal structure of the complex of F360L PPARgamma mutant with the ligand LT175
ComponentsPeroxisome proliferator-activated receptor gamma
KeywordsTRANSCRIPTION/TRANSCRIPTION inhibitor / transcription factor / RXRalpha / TRANSCRIPTION-TRANSCRIPTION inhibitor complex
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
(2S)-2-(biphenyl-4-yloxy)-3-phenylpropanoic acid / Peroxisome proliferator-activated receptor gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsPochetti, G. / Montanari, R. / Consalvi, V. / Chiaraluce, R. / Pasquo, A. / Capelli, D. / Loiodice, F. / Laghezza, A. / Lori, C.
Citation
Journal: Acta Crystallogr.,Sect.D / Year: 2014
Title: Structural basis of the transactivation deficiency of the human PPAR gamma F360L mutant associated with familial partial lipodystrophy.
Authors: Lori, C. / Pasquo, A. / Montanari, R. / Capelli, D. / Consalvi, V. / Chiaraluce, R. / Cervoni, L. / Loiodice, F. / Laghezza, A. / Aschi, M. / Giorgi, A. / Pochetti, G.
#1: Journal: J.Med.Chem. / Year: 2008
Title: Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could ...Title: Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design.
Authors: Montanari, R. / Saccoccia, F. / Scotti, E. / Crestani, M. / Godio, C. / Gilardi, F. / Loiodice, F. / Fracchiolla, G. / Laghezza, A. / Tortorella, P. / Lavecchia, A. / Novellino, E. / Mazza, ...Authors: Montanari, R. / Saccoccia, F. / Scotti, E. / Crestani, M. / Godio, C. / Gilardi, F. / Loiodice, F. / Fracchiolla, G. / Laghezza, A. / Tortorella, P. / Lavecchia, A. / Novellino, E. / Mazza, F. / Aschi, M. / Pochetti, G.
History
DepositionJun 18, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 25, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2016Group: Database references
Revision 1.2Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.3Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: audit_author / chem_comp_atom ...audit_author / chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim / struct_ref_seq_dif / struct_site
Item: _audit_author.name / _database_2.pdbx_DOI ..._audit_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Sep 20, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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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)63,3904
Polymers62,7532
Non-polymers6372
Water4,089227
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6390 Å2
ΔGint-45 kcal/mol
Surface area23890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.410, 112.460, 117.740
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: _ / Auth seq-ID: 208 - 476 / Label seq-ID: 6 - 274

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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


Mass: 31376.473 Da / Num. of mol.: 2 / Fragment: LIGAND BINDING DOMAIN (UNP RESIDUES 235-505) / Mutation: F360L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 DE3 / References: UniProt: P37231
#2: Chemical ChemComp-LRG / (2S)-2-(biphenyl-4-yloxy)-3-phenylpropanoic acid


Mass: 318.366 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / 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: 3.4 Å3/Da / Density % sol: 63.84 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 3.3 M Sodium Formate, pH 7.0, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.973 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: May 1, 2013
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.973 Å / Relative weight: 1
ReflectionResolution: 2.28→50 Å / Num. all: 39713 / Num. obs: 39713 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.088 / Net I/σ(I): 18.9
Reflection shellResolution: 2.28→2.5 Å / Rmerge(I) obs: 0.424 / Mean I/σ(I) obs: 4.8 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
AMoREphasing
CNS1.1refinement
MOSFLMdata reduction
SCALAdata scaling
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3B3K

3b3k


Resolution: 2.28→117.74 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.914 / SU B: 10.851 / SU ML: 0.145 / Cross valid method: THROUGHOUT / ESU R: 0.242 / ESU R Free: 0.21 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2576 1956 4.9 %RANDOM
Rwork0.21091 ---
obs0.21309 37723 99.74 %-
all-39204 --
Solvent computationIon probe radii: 1 Å / Shrinkage radii: 1 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.074 Å2
Baniso -1Baniso -2Baniso -3
1-2.54 Å2-0 Å20 Å2
2---0.54 Å2-0 Å2
3----2 Å2
Refinement stepCycle: LAST / Resolution: 2.28→117.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4015 0 48 227 4290
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194467
X-RAY DIFFRACTIONr_bond_other_d0.0040.024456
X-RAY DIFFRACTIONr_angle_refined_deg1.5062.0046020
X-RAY DIFFRACTIONr_angle_other_deg1.096310287
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3485539
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.55825.44193
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.6515868
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8141516
X-RAY DIFFRACTIONr_chiral_restr0.1140.2695
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024909
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02959
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it10.9333.0522162
X-RAY DIFFRACTIONr_mcbond_other10.9353.0522161
X-RAY DIFFRACTIONr_mcangle_it16.9144.5422699
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it12.4873.5782305
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 16457 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.12 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.28→2.339 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.272 173 -
Rwork0.214 2698 -
obs--99.62 %
Refinement TLS params.

T12: 0.0205 Å2 / 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)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.09160.3399-0.64181.2455-0.55882.3632-0.0151-0.1558-0.3106-0.0316-0.0214-0.10080.32640.22030.03660.0513-0.01210.090.02120.05861.41836.75744.075
22.1936-0.4255-0.49451.20211.1693.32560.03820.2864-0.281-0.03020.00990.0570.2598-0.17-0.0480.0693-0.02980.1441-0.02990.04824.57736.45313.814
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A208 - 477
2X-RAY DIFFRACTION2B207 - 477

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