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- PDB-3gd2: isoxazole ligand bound to farnesoid X receptor (FXR) -

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Basic information

Entry
Database: PDB / ID: 3gd2
Titleisoxazole ligand bound to farnesoid X receptor (FXR)
Components
  • Bile acid receptor
  • activator peptide
KeywordsTRANSCRIPTION/TRANSCRIPTION ACTIVATOR / FXR / nuclear recptor / Activator / Alternative splicing / DNA-binding / Metal-binding / Nucleus / Receptor / Repressor / Transcription / Transcription regulation / Zinc / Zinc-finger / TRANSCRIPTION-TRANSCRIPTION ACTIVATOR COMPLEX
Function / homology
Function and homology information


regulation of urea metabolic process / intracellular bile acid receptor signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / bile acid receptor activity / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid ...regulation of urea metabolic process / intracellular bile acid receptor signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / bile acid receptor activity / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid / negative regulation of very-low-density lipoprotein particle remodeling / negative regulation of interleukin-1 production / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / cellular response to organonitrogen compound / toll-like receptor 9 signaling pathway / negative regulation of monocyte chemotactic protein-1 production / intracellular receptor signaling pathway / bile acid metabolic process / nitrogen catabolite activation of transcription from RNA polymerase II promoter / cell-cell junction assembly / regulation of cholesterol metabolic process / bile acid binding / bile acid signaling pathway / negative regulation of interleukin-2 production / cellular response to fatty acid / positive regulation of interleukin-17 production / positive regulation of insulin secretion involved in cellular response to glucose stimulus / intracellular glucose homeostasis / negative regulation of interleukin-6 production / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor-mediated signaling pathway / fatty acid homeostasis / 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 / negative regulation of canonical NF-kappaB signal transduction / positive regulation of insulin receptor signaling pathway / Recycling of bile acids and salts / Notch signaling pathway / positive regulation of adipose tissue development / cholesterol homeostasis / transcription coregulator binding / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / euchromatin / SUMOylation of intracellular receptors / PPARA activates gene expression / negative regulation of inflammatory response / Nuclear Receptor transcription pathway / nuclear receptor activity / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to lipopolysaccharide / sequence-specific DNA binding / transcription by RNA polymerase II / cell differentiation / receptor complex / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / defense response to bacterium / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / innate immune response / chromatin / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / 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 ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / 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-708 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.2 Å
AuthorsMadauss, K.P. / Williams, S.P. / Deaton, D.N. / Wisely, G.B. / Mcfadyen, R.B.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064.
Authors: Bass, J.Y. / Caldwell, R.D. / Caravella, J.A. / Chen, L. / Creech, K.L. / Deaton, D.N. / Madauss, K.P. / Marr, H.B. / McFadyen, R.B. / Miller, A.B. / Parks, D.J. / Todd, D. / Williams, S.P. / Wisely, G.B.
History
DepositionFeb 23, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 7, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / 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 1.4Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bile acid receptor
B: activator peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,6783
Polymers28,0712
Non-polymers6071
Water45025
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1000 Å2
ΔGint-7 kcal/mol
Surface area11160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.749, 158.749, 158.749
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number196
Space group name H-MF23
Components on special symmetry positions
IDModelComponents
11A-3-

HOH

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Components

#1: Protein Bile acid receptor / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H ...Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H member 4 / Retinoid X receptor-interacting protein 14 / RXR-interacting protein 14


Mass: 26756.588 Da / Num. of mol.: 1 / Fragment: Farsenoid X Receptor / Mutation: C432E, C466E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96RI1
#2: Protein/peptide activator peptide


Mass: 1314.533 Da / Num. of mol.: 1 / Source method: obtained synthetically
#3: Chemical ChemComp-708 / 3-[(E)-2-(2-chloro-4-{[3-{[(R)-(2,6-dichlorophenyl)(hydroxy)-lambda~4~-sulfanyl]methyl}-5-(1-methylethyl)isoxazol-4-yl]methoxy}phenyl)ethenyl]benzoic acid


Mass: 606.944 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H26Cl3NO5S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 2.97 Å3/Da / Density % sol: 58.57 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.2M LiSO4, 25% PEG 3350, Hepes pH7.5, temperature 298K, VAPOR DIFFUSION, HANGING DROP, temperature 295K
Temp details: 295

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→50 Å / Num. obs: 5601 / % possible obs: 100 % / Redundancy: 11.2 % / Rmerge(I) obs: 0.078 / Χ2: 1.053 / Net I/σ(I): 38.41
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
3.2-3.3111.40.4015510.725100
3.31-3.4511.40.2765350.789100
3.45-3.611.40.2065700.781100
3.6-3.7911.40.1445540.857100
3.79-4.0311.40.15530.899100
4.03-4.3411.30.085561.04100
4.34-4.7811.30.0635551.151100
4.78-5.4711.30.0645601.172100
5.47-6.8911.10.0675691.21100
6.89-5010.40.0435981.921100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMAC5.2.0005refinement
PDB_EXTRACT3.006data extraction
HKL-2000data collection
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.2→47.89 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.887 / Occupancy max: 1 / Occupancy min: 0.33 / SU B: 27.834 / SU ML: 0.494 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.588 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.297 350 6.3 %RANDOM
Rwork0.238 ---
obs0.242 5597 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 105.44 Å2 / Biso mean: 79.062 Å2 / Biso min: 26.38 Å2
Refinement stepCycle: LAST / Resolution: 3.2→47.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1840 0 39 25 1904
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0221933
X-RAY DIFFRACTIONr_bond_other_d0.0010.021763
X-RAY DIFFRACTIONr_angle_refined_deg1.0231.9822634
X-RAY DIFFRACTIONr_angle_other_deg0.71334073
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4985236
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.35724.77388
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.65915302
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.222159
X-RAY DIFFRACTIONr_chiral_restr0.050.2303
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022161
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02386
X-RAY DIFFRACTIONr_nbd_refined0.2140.2501
X-RAY DIFFRACTIONr_nbd_other0.160.21799
X-RAY DIFFRACTIONr_nbtor_refined0.180.2961
X-RAY DIFFRACTIONr_nbtor_other0.0850.21055
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1340.245
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.140.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1920.231
X-RAY DIFFRACTIONr_mcbond_it0.5271.51546
X-RAY DIFFRACTIONr_mcbond_other0.0391.5478
X-RAY DIFFRACTIONr_mcangle_it0.56421911
X-RAY DIFFRACTIONr_scbond_it0.543862
X-RAY DIFFRACTIONr_scangle_it0.8344.5723
LS refinement shellResolution: 3.201→3.284 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 29 -
Rwork0.248 391 -
all-420 -
obs--100 %

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