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- PDB-1k74: The 2.3 Angstrom resolution crystal structure of the heterodimer ... -

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Basic information

Entry
Database: PDB / ID: 1k74
TitleThe 2.3 Angstrom resolution crystal structure of the heterodimer of the human PPARgamma and RXRalpha ligand binding domains respectively bound with GW409544 and 9-cis retinoic acid and co-activator peptides.
Components
  • Peroxisome proliferator activated receptor gamma
  • Retinoic acid receptor RXR-alpha
  • steroid receptor coactivator
KeywordsTRANSCRIPTION / The heterodimer of the nuclear receptor ligand binding domains of RXRalpha and PPARgamma bound respectively with 9-cis retinoic acid and GW409544 and coactivator peptides
Function / homology
Function and homology information


positive regulation of transporter activity / retinoic acid-responsive element binding / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / positive regulation of thyroid hormone receptor signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / Carnitine shuttle / retinoic acid binding / TGFBR3 expression ...positive regulation of transporter activity / retinoic acid-responsive element binding / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / positive regulation of thyroid hormone receptor signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / Carnitine shuttle / retinoic acid binding / TGFBR3 expression / labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / prostaglandin receptor activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / positive regulation of vitamin D receptor signaling pathway / negative regulation of receptor signaling pathway via STAT / positive regulation of female receptivity / MECP2 regulates transcription factors / nuclear vitamin D receptor binding / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation / positive regulation of cholesterol transport / negative regulation of cardiac muscle hypertrophy in response to stress / negative regulation of cellular response to transforming growth factor beta stimulus / positive regulation of low-density lipoprotein receptor activity / arachidonate binding / positive regulation of adiponectin secretion / lipoprotein transport / negative regulation of sequestering of triglyceride / Signaling by Retinoic Acid / DNA binding domain binding / nuclear steroid receptor activity / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / WW domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / hypothalamus development / male mating behavior / response to lipid / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / 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 blood vessel endothelial cell migration / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / cellular response to low-density lipoprotein particle stimulus / cellular response to Thyroglobulin triiodothyronine / white fat cell differentiation / negative regulation of BMP signaling pathway / Synthesis of bile acids and bile salts / cell fate commitment / positive regulation of cholesterol efflux / negative regulation of mitochondrial fission / estrous cycle / positive regulation of fat cell differentiation / negative regulation of osteoblast differentiation / negative regulation of MAPK cascade / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / BMP signaling pathway / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / positive regulation of bone mineralization / retinoic acid receptor signaling pathway / progesterone receptor signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / histone acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / cell maturation / cellular response to hormone stimulus / epithelial cell differentiation / negative regulation of signaling receptor activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / negative regulation of angiogenesis / cerebellum development / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian gene expression / negative regulation of miRNA transcription
Similarity search - Function
Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / : / Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / Peroxisome proliferator-activated receptor / Nuclear receptor coactivator, DUF1518 ...Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / : / Nuclear receptor coactivator 1 / Peroxisome proliferator-activated receptor gamma / Peroxisome proliferator-activated receptor gamma, N-terminal / PPAR gamma N-terminal region / 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 / 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 / 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-544 / (9cis)-retinoic acid / Nuclear receptor coactivator 1 / Retinoic acid receptor RXR-alpha / Peroxisome proliferator-activated receptor gamma / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsXu, H.E. / Lambert, M.H. / Montana, V.G. / Moore, L.B. / Collins, J.L. / Oplinger, J.A. / Kliewer, S.A. / Gampe Jr., R.T. / McKee, D.D. / Moore, J.T. / Willson, T.M.
CitationJournal: 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. / Plunket, K.D. / Moore, L.B. / Collins, J.L. / Oplinger, J.A. / Kliewer, S.A. / Gampe Jr., R.T. / McKee, D.D. / Moore, J.T. / Willson, T.M.
History
DepositionOct 18, 2001Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 5, 2001Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 26, 2012Group: Non-polymer description
Revision 1.4Feb 7, 2024Group: 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 / software / 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 / _software.classification / _software.name / _struct_ref_seq_dif.details / _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: Retinoic acid receptor RXR-alpha
D: Peroxisome proliferator activated receptor gamma
B: steroid receptor coactivator
E: steroid receptor coactivator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,5186
Polymers64,7074
Non-polymers8112
Water3,747208
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.62, 55.10, 214.86
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 2 molecules AD

#1: Protein Retinoic acid receptor RXR-alpha / RXRalpha


Mass: 26667.857 Da / Num. of mol.: 1 / Fragment: ligand binding domain - residues 225 - 462
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid details: T7 promoter control plasmid / Production host: Escherichia coli (E. coli) / References: UniProt: P19793
#2: Protein Peroxisome proliferator activated receptor gamma / PPARgamma


Mass: 32426.662 Da / Num. of mol.: 1 / Fragment: ligand binding domain residues - 206 - 477
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid details: T7 promoter control plasmid / Production host: Escherichia coli (E. coli) / References: UniProt: P37231

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Protein/peptide , 1 types, 2 molecules BE

#3: Protein/peptide steroid receptor coactivator


Mass: 2806.163 Da / Num. of mol.: 2 / Fragment: src-1 peptide / Source method: obtained synthetically
Details: Chemically synthesized 25mer portion of the human src-1 coactivator peptide.
References: UniProt: O43792, UniProt: Q15788*PLUS

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Non-polymers , 3 types, 210 molecules

#4: Chemical ChemComp-9CR / (9cis)-retinoic acid


Mass: 300.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H28O2 / Comment: anticancer, antineoplastic*YM
#5: Chemical ChemComp-544 / 2-(1-METHYL-3-OXO-3-PHENYL-PROPYLAMINO)-3-{4-[2-(5-METHYL-2-PHENYL-OXAZOL-4-YL)-ETHOXY]-PHENYL}-PROPIONIC ACID / GW409544


Mass: 510.580 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H30N2O5
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 208 / 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: 2.13 Å3/Da / Density % sol: 42.25 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: PEG4K, NaSCN, Ethylene Glycol, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 295K
Crystal grow
*PLUS
Details: Gampe, R.T.Jr., (2000) Mol.Cell, 5, 545.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formula
110 mg/mlprotein1drop
217 %PEG40001reservoir
3200 mM1reservoirNaSCN
48 %ethylene glycol1reservoir
58 %glycerol1reservoir

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→20 Å / Num. obs: 24986 / % possible obs: 97.3 % / Observed criterion σ(I): 0 / Rsym value: 0.057
Reflection
*PLUS
Rmerge(I) obs: 0.057
Reflection shell
*PLUS
Mean I/σ(I) obs: 3.3

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Processing

Software
NameClassification
AMoREphasing
CNXrefinement
MAR345data collection
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→20 Å / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.279 2347 9.9 %
Rwork0.238 --
all-23791 -
obs-23791 -
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4137 0 60 208 4405
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.011
X-RAY DIFFRACTIONc_angle_deg1.5
Refinement
*PLUS
σ(F): 0 / % reflection Rfree: 10 % / Rfactor obs: 0.238 / Rfactor Rfree: 0.279 / Rfactor Rwork: 0.238
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Type: c_angle_deg / Dev ideal: 1.515

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