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- PDB-5hjs: Identification of LXRbeta selective agonists for the treatment of... -

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Basic information

Entry
Database: PDB / ID: 5hjs
TitleIdentification of LXRbeta selective agonists for the treatment of Alzheimer's Disease
Components
  • Nuclear receptor coactivator 1
  • Oxysterols receptor LXR-alpha
KeywordsSIGNALING PROTEIN / Agonist / Alzheimer's
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 / regulation of lipid storage / 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 / regulation of lipid storage / positive regulation of lipoprotein lipase activity / positive regulation of toll-like receptor 4 signaling pathway / positive regulation of triglyceride biosynthetic process / positive regulation of transporter activity / 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 gluconeogenesis / positive regulation of fatty acid biosynthetic process / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / negative regulation of lipid transport / labyrinthine layer morphogenesis / positive regulation of transcription from RNA polymerase II promoter by galactose / regulation of thyroid hormone receptor signaling pathway / positive regulation of female receptivity / triglyceride homeostasis / positive regulation of cholesterol transport / apoptotic cell clearance / negative regulation of cold-induced thermogenesis / cholesterol binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / hypothalamus development / male mating behavior / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / lipid homeostasis / positive regulation of protein metabolic process / cellular response to Thyroglobulin triiodothyronine / negative regulation of macrophage derived foam cell differentiation / 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 / response to retinoic acid / positive regulation of lipid biosynthetic process / progesterone receptor signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / cellular response to hormone stimulus / histone H4K16 acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K4 acetyltransferase activity / histone H3K27 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K122 acetyltransferase activity / histone H3K18 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K12 acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / estrous cycle / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / intracellular receptor signaling pathway / negative regulation of proteolysis / estrogen receptor signaling pathway / positive regulation of adipose tissue development / hormone-mediated signaling pathway / : / lactation / Regulation of lipid metabolism by PPARalpha / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / positive regulation of neuron differentiation / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / VLDLR internalisation and degradation / Activation of gene expression by SREBF (SREBP) / cholesterol homeostasis / hippocampus development / response to progesterone / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / nuclear estrogen receptor binding / 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
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 / Nuclear receptor coactivators bHLH domain / 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-668 / Oxysterols receptor LXR-alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.72 Å
AuthorsParthasarathy, G. / Klein, D.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Identification and in Vivo Evaluation of Liver X Receptor beta-Selective Agonists for the Potential Treatment of Alzheimer's Disease.
Authors: Stachel, S.J. / Zerbinatti, C. / Rudd, M.T. / Cosden, M. / Suon, S. / Nanda, K.K. / Wessner, K. / DiMuzio, J. / Maxwell, J. / Wu, Z. / Uslaner, J.M. / Michener, M.S. / Szczerba, P. / ...Authors: Stachel, S.J. / Zerbinatti, C. / Rudd, M.T. / Cosden, M. / Suon, S. / Nanda, K.K. / Wessner, K. / DiMuzio, J. / Maxwell, J. / Wu, Z. / Uslaner, J.M. / Michener, M.S. / Szczerba, P. / Brnardic, E. / Rada, V. / Kim, Y. / Meissner, R. / Wuelfing, P. / Yuan, Y. / Ballard, J. / Holahan, M. / Klein, D.J. / Lu, J. / Fradera, X. / Parthasarathy, G. / Uebele, V.N. / Chen, Z. / Li, Y. / Li, J. / Cooke, A.J. / Bennett, D.J. / Bilodeau, M.T. / Renger, J.
History
DepositionJan 13, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 20, 2016Group: Database references
Revision 1.2Apr 27, 2016Group: Database references
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list / pdbx_struct_special_symmetry
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)72,5738
Polymers71,3454
Non-polymers1,2284
Water5,909328
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4800 Å2
ΔGint-33 kcal/mol
Surface area22830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)125.007, 125.007, 92.339
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number90
Space group name H-MP4212
Components on special symmetry positions
IDModelComponents
11C-101-

SO4

21D-101-

SO4

31A-499-

HOH

41B-511-

HOH

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Components

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


Mass: 32866.391 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H3, LXRA / Production host: Escherichia coli (E. coli) / References: UniProt: Q13133
#2: Protein/peptide Nuclear receptor coactivator 1 / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal ...NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal carcinoma antigen NY-REN-52 / Steroid receptor coactivator 1 / SRC-1


Mass: 2806.163 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-668 / 2-chloro-4-{1'-[(2R)-2-hydroxy-3-methyl-2-(trifluoromethyl)butanoyl]-4,4'-bipiperidin-1-yl}-N,N-dimethylbenzamide


Mass: 518.012 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H35ClF3N3O3
#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.: 328 / 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: 2.53 Å3/Da / Density % sol: 51.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 12% PEG MME 2000, 0.1M Ammonium Sulfate, 0.1M Tris buffer pH 7.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.933 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 17, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 1.72→63.85 Å / Num. obs: 61151 / % possible obs: 78.6 % / Redundancy: 7.1 % / Net I/σ(I): 7.4

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
REFMACphasing
RefinementResolution: 1.72→32.46 Å / Cor.coef. Fo:Fc: 0.9476 / Cor.coef. Fo:Fc free: 0.9351 / SU R Cruickshank DPI: 0.123 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.126 / SU Rfree Blow DPI: 0.12 / SU Rfree Cruickshank DPI: 0.119
RfactorNum. reflection% reflectionSelection details
Rfree0.2384 3104 5.08 %RANDOM
Rwork0.2083 ---
obs0.2099 61100 78.43 %-
Displacement parametersBiso max: 128.86 Å2 / Biso mean: 38.67 Å2 / Biso min: 12.56 Å2
Baniso -1Baniso -2Baniso -3
1--0.189 Å20 Å20 Å2
2---0.189 Å20 Å2
3---0.378 Å2
Refine analyzeLuzzati coordinate error obs: 0.234 Å
Refinement stepCycle: final / Resolution: 1.72→32.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3951 0 80 328 4359
Biso mean--51.08 47.63 -
Num. residues----482
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1497SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes111HARMONIC8
X-RAY DIFFRACTIONt_gen_planes601HARMONIC8
X-RAY DIFFRACTIONt_it4120HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion519SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5030SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4120HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5579HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion1.96
X-RAY DIFFRACTIONt_other_torsion18.14
LS refinement shellResolution: 1.72→1.76 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3417 34 4.76 %
Rwork0.3596 681 -
all0.3588 715 -
obs--78.43 %

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