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

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Basic information

Entry
Database: PDB / ID: 5hjp
TitleIdentification of LXRbeta selective agonists for the treatment of Alzheimer's Disease
Components
  • Oxysterols receptor LXR-beta
  • Retinoic acid receptor RXR-beta
KeywordsSIGNALING PROTEIN / Agonist / Alzheimer's
Function / homology
Function and homology information


positive regulation of secretion of lysosomal enzymes / positive regulation of high-density lipoprotein particle assembly / positive 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 / positive regulation of lipoprotein lipase activity / apolipoprotein A-I receptor binding / positive regulation of triglyceride biosynthetic process ...positive regulation of secretion of lysosomal enzymes / positive regulation of high-density lipoprotein particle assembly / positive 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 / positive regulation of lipoprotein lipase activity / apolipoprotein A-I receptor binding / positive regulation of triglyceride biosynthetic process / 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 lipid storage / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / positive regulation of fatty acid biosynthetic process / negative regulation of lipid transport / anatomical structure development / positive regulation of vitamin D receptor signaling pathway / negative regulation of cold-induced thermogenesis / Signaling by Retinoic Acid / nuclear steroid receptor activity / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / positive regulation of cholesterol efflux / negative regulation of macrophage derived foam cell differentiation / retinoic acid receptor signaling pathway / positive regulation of bone mineralization / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to retinoic acid / VLDLR internalisation and degradation / positive regulation of protein metabolic process / hormone-mediated signaling pathway / cholesterol homeostasis / RNA polymerase II transcription regulatory region sequence-specific DNA binding / negative regulation of proteolysis / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / PPARA activates gene expression / chromatin DNA binding / positive regulation of miRNA transcription / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / ATPase binding / DNA-binding transcription activator activity, RNA polymerase II-specific / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / chromatin / nucleolus / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Liver X receptor / Retinoid X receptor/HNF4 / 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 ...Liver X receptor / Retinoid X receptor/HNF4 / 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-668 / DI(HYDROXYETHYL)ETHER / Retinoic acid receptor RXR-beta / Oxysterols receptor LXR-beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.6 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
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

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Assembly

Deposited unit
A: Retinoic acid receptor RXR-beta
B: Oxysterols receptor LXR-beta
C: Retinoic acid receptor RXR-beta
D: Oxysterols receptor LXR-beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,2798
Polymers116,0314
Non-polymers1,2484
Water82946
1
A: Retinoic acid receptor RXR-beta
B: Oxysterols receptor LXR-beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,6404
Polymers58,0162
Non-polymers6242
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2020 Å2
ΔGint-7 kcal/mol
Surface area21940 Å2
MethodPISA
2
C: Retinoic acid receptor RXR-beta
D: Oxysterols receptor LXR-beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,6404
Polymers58,0162
Non-polymers6242
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1880 Å2
ΔGint-7 kcal/mol
Surface area20640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.770, 106.028, 139.818
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Retinoic acid receptor RXR-beta / Nuclear receptor subfamily 2 group B member 2 / Retinoid X receptor beta


Mass: 28047.273 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RXRB, NR2B2 / Production host: Escherichia coli (E. coli) / References: UniProt: P28702
#2: Protein Oxysterols receptor LXR-beta / Liver X receptor beta / Nuclear receptor NER / Nuclear receptor subfamily 1 group H member 2 / ...Liver X receptor beta / Nuclear receptor NER / Nuclear receptor subfamily 1 group H member 2 / Ubiquitously-expressed nuclear receptor


Mass: 29968.295 Da / Num. of mol.: 2 / Mutation: Q258A,R260G,D261S,R263S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H2, LXRB, NER, UNR / Production host: Escherichia coli (E. coli) / References: UniProt: P55055
#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-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 42.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 16% to 22% PEG3350, 0.2M K-Na Tartrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 30577 / % possible obs: 96.8 % / Redundancy: 3.7 % / Net I/σ(I): 16.2

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Processing

Software
NameVersionClassification
HKL-2000data scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
PHASERphasing
RefinementResolution: 2.6→35.7 Å / Cor.coef. Fo:Fc: 0.9165 / Cor.coef. Fo:Fc free: 0.875 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.366
RfactorNum. reflection% reflectionSelection details
Rfree0.2826 1525 5.06 %RANDOM
Rwork0.2358 ---
obs0.2381 30141 96.41 %-
Displacement parametersBiso max: 98.51 Å2 / Biso mean: 45.38 Å2 / Biso min: 20.78 Å2
Baniso -1Baniso -2Baniso -3
1--1.0396 Å20 Å20 Å2
2--0.7196 Å20 Å2
3---0.3199 Å2
Refine analyzeLuzzati coordinate error obs: 0.418 Å
Refinement stepCycle: final / Resolution: 2.6→35.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7549 0 84 46 7679
Biso mean--47.47 32.79 -
Num. residues----941
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2821SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes193HARMONIC8
X-RAY DIFFRACTIONt_gen_planes1127HARMONIC8
X-RAY DIFFRACTIONt_it7775HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion999SEMIHARMONIC5
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_contact9163SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7775HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg10502HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion1.75
X-RAY DIFFRACTIONt_other_torsion20.8
LS refinement shellResolution: 2.6→2.69 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3462 147 5.03 %
Rwork0.282 2774 -
all0.2852 2921 -
obs--96.41 %

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