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- PDB-1kkq: Crystal structure of the human PPAR-alpha ligand-binding domain i... -

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Basic information

Entry
Database: PDB / ID: 1kkq
TitleCrystal structure of the human PPAR-alpha ligand-binding domain in complex with an antagonist GW6471 and a SMRT corepressor motif
Components
  • NUCLEAR RECEPTOR CO-REPRESSOR 2
  • PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
KeywordsTRANSCRIPTION / nuclear corepressor nuclear hormone receptors antagonist
Function / homology
Function and homology information


positive regulation of transformation of host cell by virus / regulation of fatty acid transport / Loss of MECP2 binding ability to the NCoR/SMRT complex / regulation of fatty acid metabolic process / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / positive regulation of fatty acid oxidation / negative regulation of androgen receptor signaling pathway / regulation of cellular ketone metabolic process / cellular response to fructose stimulus ...positive regulation of transformation of host cell by virus / regulation of fatty acid transport / Loss of MECP2 binding ability to the NCoR/SMRT complex / regulation of fatty acid metabolic process / enamel mineralization / negative regulation of cell growth involved in cardiac muscle cell development / positive regulation of fatty acid oxidation / negative regulation of androgen receptor signaling pathway / regulation of cellular ketone metabolic process / cellular response to fructose stimulus / behavioral response to nicotine / nuclear glucocorticoid receptor binding / negative regulation of appetite / positive regulation of fatty acid beta-oxidation / lipoprotein metabolic process / negative regulation of hepatocyte apoptotic process / mitogen-activated protein kinase kinase kinase binding / negative regulation of leukocyte cell-cell adhesion / ubiquitin conjugating enzyme binding / Notch binding / negative regulation of glycolytic process / negative regulation of sequestering of triglyceride / nuclear steroid receptor activity / DNA-binding transcription activator activity / positive regulation of fatty acid metabolic process / nitric oxide metabolic process / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of ATP biosynthetic process / NFAT protein binding / Notch-HLH transcription pathway / negative regulation of cholesterol storage / estrous cycle / negative regulation of macrophage derived foam cell differentiation / Regulation of MECP2 expression and activity / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / negative regulation of cytokine production involved in inflammatory response / epidermis development / phosphatase binding / MDM2/MDM4 family protein binding / positive regulation of lipid biosynthetic process / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / negative regulation of signaling receptor activity / negative regulation of reactive oxygen species biosynthetic process / positive regulation of gluconeogenesis / response to organonitrogen compound / RORA activates gene expression / transcription repressor complex / cellular response to starvation / negative regulation of blood pressure / lactation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cerebellum development / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / fatty acid metabolic process / Activation of gene expression by SREBF (SREBP) / negative regulation of miRNA transcription / gluconeogenesis / HDACs deacetylate histones / Downregulation of SMAD2/3:SMAD4 transcriptional activity / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / response to insulin / SUMOylation of intracellular receptors / Heme signaling / wound healing / Transcriptional activation of mitochondrial biogenesis / regulation of circadian rhythm / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / negative regulation of inflammatory response / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / nuclear matrix / DNA-binding transcription repressor activity, RNA polymerase II-specific / Transcriptional regulation of white adipocyte differentiation / HCMV Early Events / Nuclear Receptor transcription pathway / histone deacetylase binding / transcription corepressor activity / nuclear receptor activity / Circadian Clock / response to estradiol / heart development / DNA-binding transcription activator activity, RNA polymerase II-specific / response to ethanol / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / cell differentiation / response to hypoxia / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity
Similarity search - Function
N-CoR, GPS2-interacting domain / G-protein pathway suppressor 2-interacting domain / Peroxisome proliferator-activated receptor alpha / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / Peroxisome proliferator-activated receptor / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain ...N-CoR, GPS2-interacting domain / G-protein pathway suppressor 2-interacting domain / Peroxisome proliferator-activated receptor alpha / SANT domain profile. / SANT domain / Myb domain / Myb-like DNA-binding domain / Peroxisome proliferator-activated receptor / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Retinoid X Receptor / Retinoid X Receptor / Homeobox-like domain superfamily / 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
Chem-471 / Peroxisome proliferator-activated receptor alpha / Nuclear receptor corepressor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsXu, H.E. / Stanley, T.B. / Montana, V.G. / Lambert, M.H. / Shearer, B.G. / Cobb, J.E. / McKee, D.D. / Galardi, C.M. / Nolte, R.T. / Parks, D.J.
Citation
Journal: Nature / Year: 2002
Title: Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha.
Authors: Xu, H.E. / Stanley, T.B. / Montana, V.G. / Lambert, M.H. / Shearer, B.G. / Cobb, J.E. / McKee, D.D. / Galardi, C.M. / Plunket, K.D. / Nolte, R.T. / Parks, D.J. / Moore, J.T. / Kliewer, S.A. ...Authors: Xu, H.E. / Stanley, T.B. / Montana, V.G. / Lambert, M.H. / Shearer, B.G. / Cobb, J.E. / McKee, D.D. / Galardi, C.M. / Plunket, K.D. / Nolte, R.T. / Parks, D.J. / Moore, J.T. / Kliewer, S.A. / Willson, T.M. / Stimmel, J.B.
#1: Journal: Proc.Natl.Acad.Sci.USA / Year: 2001
Title: Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors
Authors: Xu, H.E. / Lambert, M.H. / Montana, V.G. / Willson, T.M.
History
DepositionDec 10, 2001Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 20, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Sep 18, 2013Group: Derived calculations
Revision 1.4Feb 1, 2017Group: Structure summary
Revision 1.5Oct 11, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.6Aug 16, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
B: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
C: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
D: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
E: NUCLEAR RECEPTOR CO-REPRESSOR 2
F: NUCLEAR RECEPTOR CO-REPRESSOR 2
G: NUCLEAR RECEPTOR CO-REPRESSOR 2
H: NUCLEAR RECEPTOR CO-REPRESSOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,21212
Polymers130,7338
Non-polymers2,4794
Water5,945330
1
A: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
E: NUCLEAR RECEPTOR CO-REPRESSOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3033
Polymers32,6832
Non-polymers6201
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3390 Å2
ΔGint-31 kcal/mol
Surface area14870 Å2
MethodPISA
2
B: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
F: NUCLEAR RECEPTOR CO-REPRESSOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3033
Polymers32,6832
Non-polymers6201
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3360 Å2
ΔGint-29 kcal/mol
Surface area15550 Å2
MethodPISA
3
C: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
G: NUCLEAR RECEPTOR CO-REPRESSOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3033
Polymers32,6832
Non-polymers6201
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3120 Å2
ΔGint-24 kcal/mol
Surface area15230 Å2
MethodPISA
4
D: PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR
H: NUCLEAR RECEPTOR CO-REPRESSOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3033
Polymers32,6832
Non-polymers6201
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3280 Å2
ΔGint-27 kcal/mol
Surface area15020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.409, 112.773, 123.954
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR / PPAR-alpha ligand-binding domain


Mass: 30442.582 Da / Num. of mol.: 4 / Fragment: PPAR-alpha LBD
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: human / Plasmid: PRSETA / Species (production host): Escherichia coli / Organ (production host): LIVER / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21 DE3 / References: UniProt: Q07869
#2: Protein/peptide
NUCLEAR RECEPTOR CO-REPRESSOR 2 / nuclear corepressor SMRT C-terminal receptor interacting motif


Mass: 2240.667 Da / Num. of mol.: 4 / Fragment: SMRT receptor interacting motif / Source method: obtained synthetically
Details: SMRT receptor interacting motif: This sequence occurs naturally in humans.
References: UniProt: Q9Y618
#3: Chemical
ChemComp-471 / N-((2S)-2-({(1Z)-1-METHYL-3-OXO-3-[4-(TRIFLUOROMETHYL) PHENYL]PROP-1-ENYL}AMINO)-3-{4-[2-(5-METHYL-2-PHENYL-1,3-OXAZOL-4-YL)ETHOXY]PHENYL}PROPYL)PROPANAMIDE


Mass: 619.673 Da / Num. of mol.: 4 / Fragment: PPAR-alpha antagonist / Source method: obtained synthetically / Formula: C35H36F3N3O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 330 / 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: 2.76 Å3/Da / Density % sol: 55.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: PEG35K, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K
Crystal grow
*PLUS
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
15.5-9.6 %PEG350001reservoir
250 mMdi-ammonium hydrogen citrate1reservoirpH4.9
350 mMBTP1reservoirpH7.0
410 %MPD1reservoir
59.0 mg/mlprotein1drop

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Mar 24, 2001
RadiationMonochromator: Monochromator crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→20.99 Å / Num. all: 29727 / Num. obs: 29380 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4 % / Biso Wilson estimate: 50 Å2 / Rmerge(I) obs: 0.023004 / Rsym value: 0.066 / Net I/σ(I): 23.3
Reflection shellResolution: 3→3.11 Å / Redundancy: 4 % / Rmerge(I) obs: 0.158 / Mean I/σ(I) obs: 2 / Num. unique all: 2810 / Rsym value: 0.062 / % possible all: 96.1
Reflection
*PLUS
Lowest resolution: 30 Å / % possible obs: 99 % / Rmerge(I) obs: 0.068

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Processing

Software
NameVersionClassification
AMoREphasing
CNX2000refinement
MAR345data collection
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1k7L

1k7l


Resolution: 3→20.99 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 4983740.5 / Data cutoff high rms absF: 4983740.5 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.29 2335 8 %RANDOM
Rwork0.258 ---
all0.29 29737 --
obs0.29 29242 98.8 %-
Displacement parametersBiso mean: 50.1 Å2
Baniso -1Baniso -2Baniso -3
1-31.36 Å20 Å20 Å2
2---10.76 Å20 Å2
3----20.6 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.53 Å0.45 Å
Luzzati d res low-50 Å
Luzzati sigma a0.6 Å0.55 Å
Refinement stepCycle: LAST / Resolution: 3→20.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9096 0 180 330 9606
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg2
X-RAY DIFFRACTIONc_dihedral_angle_d24.5
X-RAY DIFFRACTIONc_improper_angle_d1.05
X-RAY DIFFRACTIONc_mcbond_it1.581.5
X-RAY DIFFRACTIONc_mcangle_it2.892
X-RAY DIFFRACTIONc_scbond_it1.652
X-RAY DIFFRACTIONc_scangle_it2.852.5
LS refinement shellResolution: 3→3.19 Å / Rfactor Rfree error: 0.022 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.421 367 7.9 %
Rwork0.386 4271 -
obs--95.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMINFILE_1
X-RAY DIFFRACTION2WATER_REP.PARAMINFILE_2
X-RAY DIFFRACTION3LOCALPARM.XPLINFILE_3
X-RAY DIFFRACTION4BSXPI3_BOND.XPLINFILE_4
X-RAY DIFFRACTION5INFILE_5
Software
*PLUS
Name: CNX2000 / Classification: refinement
Refinement
*PLUS
Lowest resolution: 30 Å / σ(F): 0 / % reflection Rfree: 10 % / Rfactor obs: 0.257 / Rfactor Rfree: 0.29
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 50.1 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_angle_deg1.956
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg24.5
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.05
X-RAY DIFFRACTIONc_mcbond_it1.581.5
X-RAY DIFFRACTIONc_scbond_it1.652
X-RAY DIFFRACTIONc_mcangle_it2.892
X-RAY DIFFRACTIONc_scangle_it2.852.5
LS refinement shell
*PLUS
Rfactor Rfree: 0.421 / % reflection Rfree: 7.9 % / Rfactor Rwork: 0.386

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