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Yorodumi- PDB-5i4v: Discovery of novel, orally efficacious Liver X Receptor (LXR) bet... -
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-Basic information
Entry | Database: PDB / ID: 5i4v | ||||||
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Title | Discovery of novel, orally efficacious Liver X Receptor (LXR) beta agonists | ||||||
Components |
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Keywords | DNA BINDING PROTEIN / LXRbeta-LBD / RXRbeta-LBD / heterodimer / agonist | ||||||
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 / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / locomotor rhythm / aryl hydrocarbon receptor binding / positive regulation of cholesterol efflux / negative regulation of macrophage derived foam cell differentiation / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / retinoic acid receptor signaling pathway / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / positive regulation of bone mineralization / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear retinoid X receptor binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to retinoic acid / Recycling of bile acids and salts / regulation of cellular response to insulin stimulus / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / VLDLR internalisation and degradation / positive regulation of protein metabolic process / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cholesterol homeostasis / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / response to progesterone / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / negative regulation of proteolysis / circadian regulation of gene expression / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / positive regulation of miRNA transcription / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / Circadian Clock / sequence-specific double-stranded DNA binding / HATs acetylate histones / ATPase binding / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / cell differentiation / transcription coactivator activity / protein dimerization activity / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / negative regulation of DNA-templated transcription / chromatin binding / chromatin / nucleolus / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å | ||||||
Authors | Chen, G. / McKeever, B.M. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2016 Title: Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) beta Agonist. Authors: Zheng, Y. / Zhuang, L. / Fan, K.Y. / Tice, C.M. / Zhao, W. / Dong, C. / Lotesta, S.D. / Leftheris, K. / Lindblom, P.R. / Liu, Z. / Shimada, J. / Noto, P.B. / Meng, S. / Hardy, A. / Howard, L. ...Authors: Zheng, Y. / Zhuang, L. / Fan, K.Y. / Tice, C.M. / Zhao, W. / Dong, C. / Lotesta, S.D. / Leftheris, K. / Lindblom, P.R. / Liu, Z. / Shimada, J. / Noto, P.B. / Meng, S. / Hardy, A. / Howard, L. / Krosky, P. / Guo, J. / Lipinski, K. / Kandpal, G. / Bukhtiyarov, Y. / Zhao, Y. / Lala, D. / Van Orden, R. / Zhou, J. / Chen, G. / Wu, Z. / McKeever, B.M. / McGeehan, G.M. / Gregg, R.E. / Claremon, D.A. / Singh, S.B. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5i4v.cif.gz | 200.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5i4v.ent.gz | 157.6 KB | Display | PDB format |
PDBx/mmJSON format | 5i4v.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/i4/5i4v ftp://data.pdbj.org/pub/pdb/validation_reports/i4/5i4v | HTTPS FTP |
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-Related structure data
Related structure data | 1uhlS S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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Unit cell |
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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments: Component-ID: 0 / Refine code: 0
NCS ensembles :
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-Components
#1: Protein | Mass: 30567.936 Da / Num. of mol.: 2 Mutation: Q259A, R261G, D262S, R264S,Q259A, R261G, D262S, R264S,Q259A, R261G, D262S, R264S,Q259A, R261G, D262S, R264S Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H2, LXRB, NER, UNR, NCOA2, BHLHE75, SRC2, TIF2 / Plasmid: pET28a(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P55055, UniProt: Q15596 #2: Protein | Mass: 28114.312 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: RXRB, NR2B2, NCOA2, BHLHE75, SRC2, TIF2 / Plasmid: pET21a(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P28702, UniProt: Q15596 #3: Chemical | #4: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.12 Å3/Da / Density % sol: 41.99 % |
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Crystal grow | Temperature: 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. |
-Data collection
Diffraction | Mean temperature: 100 K / Ambient temp details: CryoJet |
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Diffraction source | Source: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 8, 2011 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.075 Å / Relative weight: 1 |
Reflection | Resolution: 2.609→82.67 Å / Num. obs: 29640 / % possible obs: 95.25 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 12.2 % / Biso Wilson estimate: 59.14 Å2 / Net I/σ(I): 13.3 |
Reflection shell | Resolution: 2.609→2.68 Å / Redundancy: 5.5 % / Mean I/σ(I) obs: 1.24 / % possible all: 71.3 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1UHL Resolution: 2.61→47.72 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.924 / SU B: 33.343 / SU ML: 0.315 / Cross valid method: THROUGHOUT / ESU R Free: 0.349 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 47.114 Å2
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Refinement step | Cycle: LAST / Resolution: 2.61→47.72 Å
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Refine LS restraints |
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