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- PDB-5kyj: Brain penetrant liver X receptor (LXR) modulators based on a 2,4,... -

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Basic information

Entry
Database: PDB / ID: 5kyj
TitleBrain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core
Components
  • Oxysterols receptor LXR-beta
  • Retinoic acid receptor RXR-beta
KeywordsDNA BINDING PROTEIN / Nuclear receptors / Liver X Receptor / Retinoic Acid X Receptor / LXRbeta-LBD/RXRbeta-LBD heterodimer / Chemical modulators
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-6Y8 / Retinoic acid receptor RXR-beta / Oxysterols receptor LXR-beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsChen, G. / McKeever, B.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core.
Authors: Tice, C.M. / Noto, P.B. / Fan, K.Y. / Zhao, W. / Lotesta, S.D. / Dong, C. / Marcus, A.P. / Zheng, Y.J. / Chen, G. / Wu, Z. / Van Orden, R. / Zhou, J. / Bukhtiyarov, Y. / Zhao, Y. / Lipinski, ...Authors: Tice, C.M. / Noto, P.B. / Fan, K.Y. / Zhao, W. / Lotesta, S.D. / Dong, C. / Marcus, A.P. / Zheng, Y.J. / Chen, G. / Wu, Z. / Van Orden, R. / Zhou, J. / Bukhtiyarov, Y. / Zhao, Y. / Lipinski, K. / Howard, L. / Guo, J. / Kandpal, G. / Meng, S. / Hardy, A. / Krosky, P. / Gregg, R.E. / Leftheris, K. / McKeever, B.M. / Singh, S.B. / Lala, D. / McGeehan, G.M. / Zhuang, L. / Claremon, D.A.
History
DepositionJul 21, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2016Group: Database references
Revision 1.2Aug 9, 2017Group: Database references / Derived calculations / Category: citation / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Nov 1, 2017Group: Author supporting evidence / Category: pdbx_struct_assembly_auth_evidence
Revision 1.4Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Oxysterols receptor LXR-beta
B: Retinoic acid receptor RXR-beta
E: Oxysterols receptor LXR-beta
F: Retinoic acid receptor RXR-beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,2826
Polymers121,4194
Non-polymers8632
Water724
1
A: Oxysterols receptor LXR-beta
B: Retinoic acid receptor RXR-beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,1413
Polymers60,7092
Non-polymers4311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1810 Å2
ΔGint-9 kcal/mol
Surface area21660 Å2
MethodPISA
2
E: Oxysterols receptor LXR-beta
F: Retinoic acid receptor RXR-beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,1413
Polymers60,7092
Non-polymers4311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1790 Å2
ΔGint-10 kcal/mol
Surface area21460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.920, 100.930, 145.900
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21E
12B
22F

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11VALVALASPASPAA218 - 47725 - 284
21VALVALASPASPEC218 - 47725 - 284
12GLUGLUGLNGLNBB297 - 5436 - 252
22GLUGLUGLNGLNFD297 - 5436 - 252

NCS ensembles :
ID
1
2
DetailsDimer confirmed by size exclusion chromatography

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Components

#1: 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: 32457.008 Da / Num. of mol.: 2 / Mutation: G213H, E214M, Q259A, R261G, D262S, R264S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H2, LXRB, NER, UNR / Plasmid: pCOLADuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P55055
#2: Protein Retinoic acid receptor RXR-beta / Nuclear receptor subfamily 2 group B member 2 / Retinoid X receptor beta


Mass: 28252.461 Da / Num. of mol.: 2 / Mutation: G293M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RXRB, NR2B2 / Plasmid: pCOLADuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P28702
#3: Chemical ChemComp-6Y8 / (6~{R})-5-(5-fluoranyl-2-methoxy-pyrimidin-4-yl)-2-(3-methylsulfonylphenyl)-6-propan-2-yl-4,6-dihydropyrrolo[3,4-c]pyrazole


Mass: 431.484 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H22FN5O3S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 2.12 Å3/Da / Density % sol: 41.98 % / Description: Rods 50 to 100um long
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 1uL of scLXRbeta-LBD/scRXRbeta-LBD @ 10 mg protein/ml in 20 mM Tris-HCl pH 8.0, 150 mM NaCl, 5 mM DTT containing 1mM ligand and less than 2%(v/v) DMSO was mixed with 1uL of reservoir ...Details: 1uL of scLXRbeta-LBD/scRXRbeta-LBD @ 10 mg protein/ml in 20 mM Tris-HCl pH 8.0, 150 mM NaCl, 5 mM DTT containing 1mM ligand and less than 2%(v/v) DMSO was mixed with 1uL of reservoir solution (0.2M LiCl, 16-20%(w/v) PEG3350, 7-10%(v/v) ethylene glycol, 0.01M Strontium chloride) on a circular, silanized glass cover slide and inverted and sealed with silicon grease over a well of 200uL of reservoir solution. Crystallization plates were incubated at 23 deg C for 2-5 days before rods would appear measuring 50 to 100um long.
PH range: 7.5 - 8.5

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: CryoJet - Nitrogen gas
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 18, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.8→43.81 Å / Num. obs: 24770 / % possible obs: 99.82 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.6 % / Biso Wilson estimate: 56.6 Å2 / Net I/σ(I): 19.4
Reflection shellResolution: 2.8→2.872 Å / Redundancy: 7.8 % / Mean I/σ(I) obs: 2.47 / % possible all: 99.57

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Processing

Software
NameVersionClassification
REFMAC5.8.0071refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I4V

5i4v


Resolution: 2.8→43.81 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.903 / SU B: 16.09 / SU ML: 0.312 / Cross valid method: THROUGHOUT / ESU R Free: 0.398 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2528 1290 5 %RANDOM
Rwork0.19865 ---
obs0.20134 24770 99.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 56.58 Å2
Baniso -1Baniso -2Baniso -3
1--0.07 Å2-0 Å20 Å2
2--0.04 Å2-0 Å2
3---0.03 Å2
Refinement stepCycle: 1 / Resolution: 2.8→43.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7501 0 60 4 7565
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0197692
X-RAY DIFFRACTIONr_bond_other_d0.0030.027631
X-RAY DIFFRACTIONr_angle_refined_deg1.5121.98610391
X-RAY DIFFRACTIONr_angle_other_deg0.961317498
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6265917
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.07323.593359
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.558151414
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.611566
X-RAY DIFFRACTIONr_chiral_restr0.0720.21187
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0218484
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021764
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.6745.363707
X-RAY DIFFRACTIONr_mcbond_other3.6755.3593706
X-RAY DIFFRACTIONr_mcangle_it5.7588.0164611
X-RAY DIFFRACTIONr_mcangle_other5.7578.0174612
X-RAY DIFFRACTIONr_scbond_it4.4035.8993985
X-RAY DIFFRACTIONr_scbond_other4.4035.8983986
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.1218.6435781
X-RAY DIFFRACTIONr_long_range_B_refined9.37742.1688743
X-RAY DIFFRACTIONr_long_range_B_other9.37642.1688744
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A15241
12E15241
21B13372
22F13372
LS refinement shellResolution: 2.8→2.872 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.396 91 -
Rwork0.297 1756 -
obs--99.57 %

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