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- PDB-3ipu: X-ray structure of benzisoxazole urea synthetic agonist bound to ... -

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Basic information

Entry
Database: PDB / ID: 3ipu
TitleX-ray structure of benzisoxazole urea synthetic agonist bound to the LXR-alpha
Components
  • Nuclear receptor coactivator 1
  • Oxysterols receptor LXR-alpha
KeywordsTRANSCRIPTION / Nuclear receptor / LXR homodimer / LXR signaling / Alternative splicing / DNA-binding / Metal-binding / Nucleus / Polymorphism / Receptor / Transcription regulation / Zinc / Zinc-finger / Activator / Acyltransferase / Chromosomal rearrangement / Isopeptide bond / Phosphoprotein / Proto-oncogene / Transferase / Ubl conjugation
Function / homology
Function and homology information


negative regulation of secretion of lysosomal enzymes / sterol response element binding / negative regulation of macrophage activation / negative regulation of pancreatic juice secretion / phosphatidylcholine acyl-chain remodeling / negative regulation of response to endoplasmic reticulum stress / negative regulation of pinocytosis / sterol homeostasis / positive regulation of toll-like receptor 4 signaling pathway / positive regulation of lipoprotein lipase activity ...negative regulation of secretion of lysosomal enzymes / sterol response element binding / negative regulation of macrophage activation / negative regulation of pancreatic juice secretion / phosphatidylcholine acyl-chain remodeling / negative regulation of response to endoplasmic reticulum stress / negative regulation of pinocytosis / sterol homeostasis / positive regulation of toll-like receptor 4 signaling pathway / positive regulation of lipoprotein lipase activity / positive regulation of triglyceride biosynthetic process / positive regulation of transporter activity / 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 / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / positive regulation of fatty acid biosynthetic process / negative regulation of lipid transport / 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 / triglyceride homeostasis / positive regulation of cholesterol transport / apoptotic cell clearance / negative regulation of cold-induced thermogenesis / cholesterol binding / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / hypothalamus development / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / lipid homeostasis / negative regulation of macrophage derived foam cell differentiation / cellular response to Thyroglobulin triiodothyronine / Synthesis of bile acids and bile salts / positive regulation of cholesterol efflux / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / progesterone receptor signaling pathway / positive regulation of lipid biosynthetic process / response to retinoic acid / histone acetyltransferase activity / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Recycling of bile acids and salts / cellular response to hormone stimulus / histone acetyltransferase / estrous cycle / 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 / positive regulation of protein metabolic process / lactation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / positive regulation of neuron differentiation / VLDLR internalisation and degradation / BMAL1:CLOCK,NPAS2 activates circadian gene expression / cerebellum development / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / : / cholesterol homeostasis / nuclear receptor binding / response to progesterone / negative regulation of proteolysis / nuclear estrogen receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / hippocampus development / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / regulation of circadian rhythm / Cytoprotection by HMOX1 / cerebral cortex development / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / negative regulation of inflammatory response / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / male gonad development / Circadian Clock / response to estradiol / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to lipopolysaccharide / Estrogen-dependent gene expression / transcription regulator complex / transcription coactivator activity / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / receptor complex
Similarity search - Function
Liver X receptor / Nuclear receptor coactivator 1 / 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 ...Liver X receptor / Nuclear receptor coactivator 1 / 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 / 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-O40 / Oxysterols receptor LXR-alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsFradera, X. / Vu, D. / Nimz, O. / Skene, R. / Hosfield, D. / Wijnands, R. / Cooke, A.J. / Haunso, A. / King, A. / Bennet, D.J. ...Fradera, X. / Vu, D. / Nimz, O. / Skene, R. / Hosfield, D. / Wijnands, R. / Cooke, A.J. / Haunso, A. / King, A. / Bennet, D.J. / McGuire, R. / Uitdehaag, J.C.M.
CitationJournal: J.Mol.Biol. / Year: 2010
Title: X-ray structures of the LXRalpha LBD in its homodimeric form and implications for heterodimer signaling.
Authors: Fradera, X. / Vu, D. / Nimz, O. / Skene, R. / Hosfield, D. / Wynands, R. / Cooke, A.J. / Haunso, A. / King, A. / Bennett, D.J. / McGuire, R. / Uitdehaag, J.C.
History
DepositionAug 18, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_special_symmetry / 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 1.3Apr 3, 2024Group: 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: Oxysterols receptor LXR-alpha
B: Oxysterols receptor LXR-alpha
C: Nuclear receptor coactivator 1
D: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,4968
Polymers71,3454
Non-polymers1,1514
Water1,53185
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4910 Å2
ΔGint-32 kcal/mol
Surface area23340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)125.178, 125.178, 92.957
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number90
Space group name H-MP4212
Components on special symmetry positions
IDModelComponents
11B-802-

SO4

21C-802-

SO4

31A-24-

HOH

41B-4-

HOH

DetailsBIOLOGICAL UNIT IS A DIMER

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Components

#1: Protein Oxysterols receptor LXR-alpha / Liver X receptor alpha / Nuclear orphan receptor LXR-alpha / Nuclear receptor subfamily 1 group H member 3


Mass: 32866.391 Da / Num. of mol.: 2 / Fragment: Ligand binding domain: UNP residues 182-447
Source method: isolated from a genetically manipulated source
Details: Syrrx, clone SECC-7959 / Source: (gene. exp.) Homo sapiens (human) / Gene: LXRA, NR1H3 / Plasmid: pSX29 / Production host: Escherichia coli (E. coli) / Strain (production host): DH10-T1r / References: UniProt: Q13133
#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: 2806.163 Da / Num. of mol.: 2
Fragment: Steroid receptor co-activator 1: UNP residues 676-700
Source method: obtained synthetically
Details: SRC-1 peptide from MilliQ with the sequence based on UniProt entry Q15788 (NCOA1_HUMAN), residues 676-700.
References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-O40 / 4-{[methyl(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)carbamoyl]amino}benzoic acid


Mass: 479.449 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24F3N3O5
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 85 / 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: 2.55 Å3/Da / Density % sol: 51.8 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 10% PEG MME 2000, 100mM (NH4)2SO4, 40mM Tris-HCl pH 7.8, 60mM Imidazole pH 6.2, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Nov 29, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→29.66 Å / Num. all: 26580 / Num. obs: 26580

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In-house LXR-alpha complex

Resolution: 2.4→29.66 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.891 / SU B: 7.976 / SU ML: 0.192 / Cross valid method: THROUGHOUT / ESU R: 0.416 / ESU R Free: 0.293 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29101 1375 5.2 %RANDOM
Rwork0.234 ---
obs0.23698 25203 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.508 Å2
Baniso -1Baniso -2Baniso -3
1-0.23 Å20 Å20 Å2
2--0.23 Å20 Å2
3----0.47 Å2
Refinement stepCycle: LAST / Resolution: 2.4→29.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4128 0 78 85 4291
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0224278
X-RAY DIFFRACTIONr_bond_other_d0.0010.022958
X-RAY DIFFRACTIONr_angle_refined_deg1.1751.9795787
X-RAY DIFFRACTIONr_angle_other_deg0.90237169
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0525499
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.84323.657216
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.88315760
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5621538
X-RAY DIFFRACTIONr_chiral_restr0.0630.2641
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024654
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02880
X-RAY DIFFRACTIONr_nbd_refined0.2030.2969
X-RAY DIFFRACTIONr_nbd_other0.180.23012
X-RAY DIFFRACTIONr_nbtor_refined0.1750.22065
X-RAY DIFFRACTIONr_nbtor_other0.0860.22112
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1610.2124
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0790.25
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2010.228
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.160.219
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8821.53310
X-RAY DIFFRACTIONr_mcbond_other0.111.5990
X-RAY DIFFRACTIONr_mcangle_it0.96624091
X-RAY DIFFRACTIONr_scbond_it1.38732002
X-RAY DIFFRACTIONr_scangle_it2.0764.51695
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 107 -
Rwork0.244 1948 -
obs--100 %

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