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- PDB-3ipq: X-ray structure of GW3965 synthetic agonist bound to the LXR-alpha -

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Basic information

Entry
Database: PDB / ID: 3ipq
TitleX-ray structure of GW3965 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 pancreatic juice secretion / phosphatidylcholine acyl-chain remodeling / positive regulation of cholesterol transport / negative regulation of response to endoplasmic reticulum stress / negative regulation of pinocytosis / negative regulation of macrophage activation / sterol homeostasis / positive regulation of toll-like receptor 4 signaling pathway ...negative regulation of secretion of lysosomal enzymes / sterol response element binding / negative regulation of pancreatic juice secretion / phosphatidylcholine acyl-chain remodeling / positive regulation of cholesterol transport / negative regulation of response to endoplasmic reticulum stress / negative regulation of pinocytosis / negative regulation of macrophage activation / 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 mediated signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / triglyceride homeostasis / apoptotic cell clearance / positive regulation of female receptivity / negative regulation of cold-induced thermogenesis / cholesterol binding / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / lipid homeostasis / negative regulation of macrophage derived foam cell differentiation / estrous cycle / cellular response to Thyroglobulin triiodothyronine / Synthesis of bile acids and bile salts / positive regulation of cholesterol efflux / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / positive regulation of lipid biosynthetic process / response to retinoic acid / histone acetyltransferase activity / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / VLDLR internalisation and degradation / lactation / positive regulation of protein metabolic process / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / response to progesterone / cholesterol homeostasis / nuclear estrogen receptor binding / nuclear receptor binding / hippocampus development / negative regulation of proteolysis / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / regulation of circadian rhythm / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / cerebral cortex development / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / male gonad development / nuclear receptor activity / Circadian Clock / response to estradiol / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / cellular response to lipopolysaccharide / transcription regulator complex / cell differentiation / transcription coactivator activity / receptor complex / transcription cis-regulatory region binding / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / positive regulation of apoptotic process
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 / 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. / Nuclear receptor coactivator, interlocking / 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-965 / Oxysterols receptor LXR-alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 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: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3514
Polymers35,6732
Non-polymers6782
Water2,126118
1
A: Oxysterols receptor LXR-alpha
B: Nuclear receptor coactivator 1
hetero molecules

A: Oxysterols receptor LXR-alpha
B: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,7018
Polymers71,3454
Non-polymers1,3564
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area4860 Å2
ΔGint-31.6 kcal/mol
Surface area21360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)125.593, 125.593, 92.405
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422
Components on special symmetry positions
IDModelComponents
11B-802-

SO4

21A-11-

HOH

31A-27-

HOH

41A-64-

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.: 1 / 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.: 1
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-965 / [3-(3-{[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino}propoxy)phenyl]acetic acid


Mass: 582.052 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H31ClF3NO3
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 118 / 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: 51.83 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 100mM (NH4)2SO4, 40mM Tris-HCl pH 7.8, 60mM Imidazole pH 6.2, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 27, 2007
RadiationMonochromator: Diamond (111), Ge(220) / Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2→15.75 Å / Num. all: 25146 / Num. obs: 25146
Reflection shellResolution: 2→2.1 Å / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In-house LXR-alpha structure

Resolution: 2→15.75 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.926 / SU B: 3.46 / SU ML: 0.098 / Cross valid method: THROUGHOUT / ESU R: 0.149 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23358 1279 5.1 %RANDOM
Rwork0.19912 ---
obs0.20085 23788 99.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.605 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å20 Å2
2--0.06 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 2→15.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1922 0 46 118 2086
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222008
X-RAY DIFFRACTIONr_bond_other_d0.0010.021382
X-RAY DIFFRACTIONr_angle_refined_deg1.4851.9892714
X-RAY DIFFRACTIONr_angle_other_deg1.00933359
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3845231
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.78724.0499
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.40215358
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6041515
X-RAY DIFFRACTIONr_chiral_restr0.0880.2303
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022166
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02411
X-RAY DIFFRACTIONr_nbd_refined0.2090.2427
X-RAY DIFFRACTIONr_nbd_other0.1850.21425
X-RAY DIFFRACTIONr_nbtor_refined0.1790.2960
X-RAY DIFFRACTIONr_nbtor_other0.0870.2986
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1510.2119
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1340.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2910.225
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1220.210
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.41.51535
X-RAY DIFFRACTIONr_mcbond_other0.2241.5461
X-RAY DIFFRACTIONr_mcangle_it1.50821907
X-RAY DIFFRACTIONr_scbond_it2.5183944
X-RAY DIFFRACTIONr_scangle_it3.6914.5807
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.263 86 -
Rwork0.217 1711 -
obs--100 %

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