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- PDB-1fm9: THE 2.1 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF THE HETERODIMER ... -

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Basic information

Entry
Database: PDB / ID: 1fm9
TitleTHE 2.1 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF THE HETERODIMER OF THE HUMAN RXRALPHA AND PPARGAMMA LIGAND BINDING DOMAINS RESPECTIVELY BOUND WITH 9-CIS RETINOIC ACID AND GI262570 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 GI262570 and co-activator 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 mediated signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / Carnitine metabolism / ion binding / Regulation of pyruvate dehydrogenase (PDH) complex ...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 mediated signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / Carnitine metabolism / ion binding / Regulation of pyruvate dehydrogenase (PDH) complex / retinoic acid binding / labyrinthine layer morphogenesis / positive regulation of vitamin D receptor signaling pathway / regulation of thyroid hormone mediated signaling pathway / 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 / positive regulation of transcription from RNA polymerase II promoter by galactose / nuclear vitamin D receptor binding / MECP2 regulates transcription factors / positive regulation of female receptivity / 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 / Signaling by Retinoic Acid / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / DNA binding domain binding / STAT family protein binding / nuclear steroid receptor activity / hypothalamus development / positive regulation of fatty acid metabolic process / 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 macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / negative regulation of lipid storage / negative regulation of blood vessel endothelial cell migration / estrous cycle / negative regulation of BMP signaling pathway / cellular response to Thyroglobulin triiodothyronine / white fat cell differentiation / negative regulation of mitochondrial fission / Synthesis of bile acids and bile salts / 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 / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / BMP signaling pathway / positive regulation of bone mineralization / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / long-chain fatty acid transport / nuclear retinoid X receptor binding / response to retinoic acid / histone acetyltransferase activity / negative regulation of signaling receptor activity / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / cell maturation / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / epithelial cell differentiation / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cerebellum development / negative regulation of angiogenesis / response to nutrient / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / 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 receptor coactivator, Ncoa-type, interlocking ...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 DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / 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
Chem-570 / (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 / Resolution: 2.1 Å
AuthorsGampe Jr., R.T. / Montana, V.G. / Lambert, M.H. / Miller, A.B. / Bledsoe, R.K. / Milburn, M.V. / Kliewer, S.A. / Willson, T.M. / Xu, H.E.
CitationJournal: Mol.Cell / Year: 2000
Title: Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors.
Authors: Gampe Jr., R.T. / Montana, V.G. / Lambert, M.H. / Miller, A.B. / Bledsoe, R.K. / Milburn, M.V. / Kliewer, S.A. / Willson, T.M. / Xu, H.E.
History
DepositionAug 16, 2000Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 16, 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 1.4Oct 4, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.5Jan 31, 2018Group: Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.6Feb 7, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _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: 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)64,2216
Polymers63,3744
Non-polymers8472
Water2,360131
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.143, 54.046, 211.149
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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


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: PACYC184 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P19793
#2: Protein PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA


Mass: 31094.135 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: PRSET / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / 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 human src-1 coactivator peptide
References: UniProt: O43793, UniProt: Q15788*PLUS

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Non-polymers , 3 types, 133 molecules

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


Mass: 300.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H28O2 / Comment: anticancer, antineoplastic*YM
#5: Chemical ChemComp-570 / 2-(2-BENZOYL-PHENYLAMINO)-3-{4-[2-(5-METHYL-2-PHENYL-OXAZOL-4-YL)-ETHOXY]-PHENYL}-PROPIONIC ACID / GI262570 / Farglitazar / Farglitazar


Mass: 546.612 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H30N2O5 / Comment: agonist*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 131 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer detailsGI262570 is a synthetic antidiabetic agonist for PPARGAMMA

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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: 2.07 Å3/Da / Density % sol: 40.72 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 17% PEG 4K, 200mM NaSCN, 8% Ethylene Glycol , pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 22K
Crystal
*PLUS
Density % sol: 35 %
Crystal grow
*PLUS
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
DetectorType: MARRESEARCH / Detector: CCD / Date: Dec 1, 1999
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→20 Å / Num. obs: 25483 / % possible obs: 98.8 % / Biso Wilson estimate: 25.3 Å2 / Rmerge(I) obs: 0.094 / Net I/σ(I): 21.2
Reflection shell
*PLUS
Mean I/σ(I) obs: 2.1

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Processing

Software
NameVersionClassification
X-PLORmodel building
CNS0.5refinement
MAR345data collection
HKL-2000data scaling
X-PLORphasing
RefinementResolution: 2.1→20 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 149063.17 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2
RfactorNum. reflection% reflectionSelection details
Rfree0.268 2895 10 %RANDOM
Rwork0.239 ---
obs0.239 29087 91.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 55 Å2 / ksol: 0.382 e/Å3
Displacement parametersBiso mean: 49 Å2
Baniso -1Baniso -2Baniso -3
1--3.73 Å20 Å20 Å2
2--6.42 Å20 Å2
3----2.69 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.33 Å0.28 Å
Luzzati d res low-5 Å
Luzzati sigma a0.3 Å0.27 Å
Refinement stepCycle: LAST / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4148 0 63 131 4342
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.013
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d20.4
X-RAY DIFFRACTIONc_improper_angle_d0.96
X-RAY DIFFRACTIONc_mcbond_it1.21.5
X-RAY DIFFRACTIONc_mcangle_it2.142
X-RAY DIFFRACTIONc_scbond_it1.412
X-RAY DIFFRACTIONc_scangle_it2.222.5
LS refinement shellResolution: 2.1→2.23 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.334 444 10.4 %
Rwork0.308 3820 -
obs--82.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2BSXPI3.XPL
X-RAY DIFFRACTION3WATER_REP.PARAM
X-RAY DIFFRACTION4570.XPL
X-RAY DIFFRACTION59CRA3.XPL
Software
*PLUS
Name: CNS / Version: 0.5 / Classification: refinement
Refinement
*PLUS
σ(F): 2 / % reflection Rfree: 10 %
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 49 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg20.4
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.96
X-RAY DIFFRACTIONc_mcbond_it1.5
X-RAY DIFFRACTIONc_scbond_it2
X-RAY DIFFRACTIONc_mcangle_it2
X-RAY DIFFRACTIONc_scangle_it2.5
LS refinement shell
*PLUS
Rfactor Rfree: 0.334 / % reflection Rfree: 10.4 % / Rfactor Rwork: 0.308

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