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- PDB-2p54: a crystal structure of PPAR alpha bound with SRC1 peptide and GW735 -

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Basic information

Entry
Database: PDB / ID: 2p54
Titlea crystal structure of PPAR alpha bound with SRC1 peptide and GW735
Components
  • Nuclear receptor coactivator 1
  • Peroxisome proliferator-activated receptor alpha
KeywordsTRANSCRIPTION / PPAR alpha GW735 SRC1 agonist HDLc
Function / homology
Function and homology information


regulation of fatty acid transport / enamel mineralization / positive regulation of fatty acid beta-oxidation / regulation of ketone metabolic process / cellular response to fructose stimulus / negative regulation of cell growth involved in cardiac muscle cell development / regulation of fatty acid metabolic process / negative regulation of appetite / negative regulation of hepatocyte apoptotic process / positive regulation of fatty acid oxidation ...regulation of fatty acid transport / enamel mineralization / positive regulation of fatty acid beta-oxidation / regulation of ketone metabolic process / cellular response to fructose stimulus / negative regulation of cell growth involved in cardiac muscle cell development / regulation of fatty acid metabolic process / negative regulation of appetite / negative regulation of hepatocyte apoptotic process / positive regulation of fatty acid oxidation / behavioral response to nicotine / lipoprotein metabolic process / negative regulation of leukocyte cell-cell adhesion / labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / mitogen-activated protein kinase kinase kinase binding / ubiquitin conjugating enzyme binding / negative regulation of glycolytic process / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of fatty acid metabolic process / NFAT protein binding / DNA-binding transcription activator activity / male mating behavior / hypothalamus development / negative regulation of cholesterol storage / nuclear steroid receptor activity / progesterone receptor signaling pathway / cellular response to Thyroglobulin triiodothyronine / positive regulation of ATP biosynthetic process / Synthesis of bile acids and bile salts / negative regulation of macrophage derived foam cell differentiation / epidermis development / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / response to retinoic acid / protein-lysine-acetyltransferase activity / positive regulation of lipid biosynthetic process / estrous cycle / nuclear retinoid X receptor binding / phosphatase binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Recycling of bile acids and salts / histone acetyltransferase / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cellular response to hormone stimulus / estrogen receptor signaling pathway / intracellular receptor signaling pathway / nitric oxide metabolic process / negative regulation of reactive oxygen species biosynthetic process / Regulation of lipid metabolism by PPARalpha / negative regulation of blood pressure / lactation / peroxisome proliferator activated receptor signaling pathway / response to progesterone / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / positive regulation of adipose tissue development / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian expression / positive regulation of neuron differentiation / negative regulation of cytokine production involved in inflammatory response / MDM2/MDM4 family protein binding / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / positive regulation of gluconeogenesis / negative regulation of miRNA transcription / cerebellum development / cellular response to starvation / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / nuclear estrogen receptor binding / nuclear receptor binding / gluconeogenesis / RNA polymerase II transcription regulatory region sequence-specific DNA binding / hippocampus development / SUMOylation of intracellular receptors / circadian regulation of gene expression / wound healing / Heme signaling / negative regulation of transforming growth factor beta receptor signaling pathway / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / Cytoprotection by HMOX1 / fatty acid metabolic process / regulation of circadian rhythm / cerebral cortex development / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / response to insulin / mRNA transcription by RNA polymerase II / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / male gonad development / nuclear receptor activity / transcription coactivator binding / RNA polymerase II transcription regulator complex
Similarity search - Function
Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain ...Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / : / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / Nuclear receptor coactivators bHLH domain / PAS domain / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / : / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / PAS 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-735 / Peroxisome proliferator-activated receptor alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsXu, R.X. / Xu, H.E. / Sierra, M.L. / Montana, V.G. / Lambert, M.H. / Pianetti, P.M.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Substituted 2-[(4-Aminomethyl)phenoxy]-2-methylpropionic Acid PPAR Agonists. 1.Discovery of a Novel Series of Potent HDLc Raising Agents.
Authors: Sierra, M.L. / Beneton, V. / Boullay, A.B. / Boyer, T. / Brewster, A. / Donche, F. / Forest, M.C. / Fouchet, M.H. / Gellibert, F.J. / Grillot, D.A. / Lambert, M.H. / Laroze, A. / Grumelec, C. ...Authors: Sierra, M.L. / Beneton, V. / Boullay, A.B. / Boyer, T. / Brewster, A. / Donche, F. / Forest, M.C. / Fouchet, M.H. / Gellibert, F.J. / Grillot, D.A. / Lambert, M.H. / Laroze, A. / Grumelec, C.L. / Linget, J.M. / Montana, V.G. / Nguyen, V.L. / Nicodeme, E. / Patel, V. / Penfornis, A. / Pineau, O. / Pohin, D. / Potvain, F. / Paulain, G. / Ruault, C.B. / Saunders, M. / Toum, J. / Xu, H.E. / Xu, R.X. / Pianetti, P.M.
History
DepositionMar 14, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2007Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Apr 3, 2024Group: Refinement description / Category: 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 alpha
B: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2683
Polymers31,7892
Non-polymers4781
Water4,828268
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.263, 103.535, 49.850
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Peroxisome proliferator-activated receptor alpha / PPAR-alpha


Mass: 30270.402 Da / Num. of mol.: 1 / Fragment: PPAR alpha
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPARA, NR1C1, PPAR / Production host: Escherichia coli (E. coli) / References: UniProt: Q07869
#2: Protein/peptide Nuclear receptor coactivator 1 / NCoA-1 / Steroid receptor coactivator 1 / SRC-1 / RIP160 / Protein Hin-2 / Renal carcinoma antigen NY-REN-52


Mass: 1518.828 Da / Num. of mol.: 1 / Fragment: SRC1 peptide / Source method: obtained synthetically / Details: This sequence occurs naturally in humans / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-735 / 2-METHYL-2-(4-{[({4-METHYL-2-[4-(TRIFLUOROMETHYL)PHENYL]-1,3-THIAZOL-5-YL}CARBONYL)AMINO]METHYL}PHENOXY)PROPANOIC ACID


Mass: 478.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21F3N2O4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / 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: 2.49 Å3/Da / Density % sol: 50.52 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 7% PEG 3350, 200 mM NaF, 12% 2,5-hexanediol, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jul 5, 2001
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.79→20 Å / Num. all: 30633 / Num. obs: 30145 / % possible obs: 98 % / Observed criterion σ(F): 5 / Observed criterion σ(I): 5.24 / Redundancy: 7.1 % / Biso Wilson estimate: 3.2 Å2 / Rmerge(I) obs: 0.045 / Rsym value: 0.045 / Net I/σ(I): 39.45
Reflection shellResolution: 1.79→1.86 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 5.2 / Num. unique all: 2848 / Rsym value: 0.35 / % possible all: 95.8

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Processing

Software
NameClassification
HKL-2000data collection
AMoREphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: apo PPAR alpha

Resolution: 1.79→20 Å / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber / Details: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.227 1761 -RANDOM
Rwork0.204 ---
all0.205 30633 --
obs0.204 29552 96.5 %-
Displacement parametersBiso mean: 27 Å2
Baniso -1Baniso -2Baniso -3
1--0.015 Å20 Å20 Å2
2--0.01 Å20 Å2
3---0.005 Å2
Refinement stepCycle: LAST / Resolution: 1.79→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2196 0 53 268 2517
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_deg1.287
X-RAY DIFFRACTIONc_bond_d0.005

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