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- PDB-1ot7: Structural Basis for 3-deoxy-CDCA Binding and Activation of FXR -

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Basic information

Entry
Database: PDB / ID: 1ot7
TitleStructural Basis for 3-deoxy-CDCA Binding and Activation of FXR
Components
  • Bile Acid Receptor
  • dodecamer peptide fragment of RPGR-interacting protein 1
KeywordsHORMONE/GROWTH FACTOR RECEPTOR / BILE ACID / NUCLEAR RECEPTOR / COACTIVATOR / LIGAND BINDING DOMAIN / FXR / HORMONE-GROWTH FACTOR RECEPTOR COMPLEX
Function / homology
Function and homology information


response to norepinephrine / Endogenous sterols / Synthesis of bile acids and bile salts / Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / negative regulation of triglyceride biosynthetic process / regulation of carbohydrate metabolic process / regulation of lipid storage / hepatocyte proliferation ...response to norepinephrine / Endogenous sterols / Synthesis of bile acids and bile salts / Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / negative regulation of triglyceride biosynthetic process / regulation of carbohydrate metabolic process / regulation of lipid storage / hepatocyte proliferation / regulation of bile acid secretion / 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 / negative regulation of collagen biosynthetic process / bile acid receptor activity / regulation of low-density lipoprotein particle clearance / intracellular triglyceride homeostasis / cellular response to bile acid / SUMOylation of intracellular receptors / Nuclear Receptor transcription pathway / negative regulation of very-low-density lipoprotein particle remodeling / negative regulation of interleukin-1 production / leukocyte migration involved in inflammatory response / regulation of insulin secretion involved in cellular response to glucose stimulus / cellular response to organonitrogen compound / toll-like receptor 9 signaling pathway / triglyceride homeostasis / negative regulation of monocyte chemotactic protein-1 production / intracellular receptor signaling pathway / bile acid metabolic process / digestive tract development / bile acid and bile salt transport / response to cholesterol / cell-cell junction assembly / 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 / negative regulation of tumor necrosis factor-mediated signaling pathway / fatty acid homeostasis / response to glucose / nuclear retinoid X receptor binding / negative regulation of canonical NF-kappaB signal transduction / positive regulation of insulin receptor signaling pathway / Notch signaling pathway / positive regulation of adipose tissue development / response to nutrient levels / cholesterol homeostasis / liver regeneration / transcription coregulator binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / euchromatin / response to organic cyclic compound / negative regulation of inflammatory response / response to estrogen / nuclear receptor activity / cellular response to xenobiotic stimulus / glucose homeostasis / DNA-binding transcription activator activity, RNA polymerase II-specific / response to ethanol / cellular response to lipopolysaccharide / sequence-specific DNA binding / response to lipopolysaccharide / transcription by RNA polymerase II / cell differentiation / receptor complex / DNA-binding transcription factor activity, RNA polymerase II-specific / defense response to bacterium / response to xenobiotic stimulus / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / innate immune response / protein-containing complex binding / positive regulation of gene expression / 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 / DNA binding / zinc ion binding / nucleus
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
6-ETHYL-CHENODEOXYCHOLIC ACID / ISO-URSODEOXYCHOLIC ACID / Bile acid receptor
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsMi, L.Z. / Devarakonda, S. / Harp, J.M. / Han, Q. / Pellicciari, R. / Willson, T.M. / Khorasanizadeh, S. / Rastinejad, F.
CitationJournal: Mol.Cell / Year: 2003
Title: Structural Basis for Bile Acid Binding and Activation of the Nuclear Receptor FXR
Authors: Mi, L.Z. / Devarakonda, S. / Harp, J.M. / Han, Q. / Pellicciari, R. / Willson, T.M. / Khorasanizadeh, S. / Rastinejad, F.
History
DepositionMar 21, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 2, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bile Acid Receptor
B: Bile Acid Receptor
C: dodecamer peptide fragment of RPGR-interacting protein 1
D: dodecamer peptide fragment of RPGR-interacting protein 1
E: dodecamer peptide fragment of RPGR-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,7137
Polymers57,9005
Non-polymers8132
Water50428
1
A: Bile Acid Receptor
C: dodecamer peptide fragment of RPGR-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,6383
Polymers28,2172
Non-polymers4211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bile Acid Receptor
D: dodecamer peptide fragment of RPGR-interacting protein 1
E: dodecamer peptide fragment of RPGR-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,0754
Polymers29,6823
Non-polymers3931
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.536, 107.129, 69.203
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Cell settingorthorhombic
Space group name H-MP21212
DetailsThe biological assembly is one of the subunits(A or B).

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Components

#1: Protein Bile Acid Receptor / FXR / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Retinoid X receptor-interacting ...FXR / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Retinoid X receptor-interacting protein 14 / RXR-interacting protein 14


Mass: 26752.787 Da / Num. of mol.: 2 / Fragment: ligand binding domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: NR1H4 / Plasmid: pET-16b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q62735
#2: Protein/peptide dodecamer peptide fragment of RPGR-interacting protein 1


Mass: 1464.664 Da / Num. of mol.: 3 / Fragment: GRIP1 NID3 / Source method: obtained synthetically / Details: This sequence occurs naturally in humans
#3: Chemical ChemComp-CHC / 6-ETHYL-CHENODEOXYCHOLIC ACID / Obeticholic acid


Mass: 420.625 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H44O4 / Comment: medication*YM
#4: Chemical ChemComp-IU5 / ISO-URSODEOXYCHOLIC ACID


Mass: 392.572 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H40O4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 3.18 Å3/Da / Density % sol: 61 %
Crystal growTemperature: 282 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: PEG 8000, Ethylene glycol, PIPES, Ammonium Sulfate, pH 6.4, VAPOR DIFFUSION, HANGING DROP, temperature 282K
Crystal grow
*PLUS
pH: 8 / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
1400 mM1dropNaCl
210 mMimidazole1drop
310 %glycerol1drop
420 mMTris1droppH8.0
54-5 mg/mlprotein1drop
70.1 MPIPES1reservoirpH6.4
6ethylene gylcol1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A / Wavelength: 1.067 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 25, 2002
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.067 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. all: 17120 / Num. obs: 16726 / % possible obs: 97.7 % / Observed criterion σ(I): 2.5 / Redundancy: 4.7 % / Biso Wilson estimate: 44.5 Å2 / Rsym value: 0.071 / Net I/σ(I): 14.41
Reflection shellResolution: 2.9→3 Å / Redundancy: 4.8 % / Mean I/σ(I) obs: 2 / Num. unique all: 1612 / Rsym value: 0.458 / % possible all: 96.5
Reflection
*PLUS
Lowest resolution: 15 Å / Num. obs: 12668 / % possible obs: 98.9 % / Num. measured all: 99535 / Rmerge(I) obs: 0.071
Reflection shell
*PLUS
Highest resolution: 2.9 Å / Lowest resolution: 3 Å / % possible obs: 99.6 % / Rmerge(I) obs: 0.458

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
MOLREPphasing
CNS1.1refinement
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: RAR LBD

Resolution: 2.9→19.96 Å / Rfactor Rfree error: 0.009 / Isotropic thermal model: GROUP / Cross valid method: THROUGHOUT / σ(F): 3 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.279 880 6.9 %RANDOM
Rwork0.233 ---
all0.236 16938 --
obs0.2331 12771 75.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 18.1809 Å2 / ksol: 0.244014 e/Å3
Displacement parametersBiso mean: 82.9 Å2
Baniso -1Baniso -2Baniso -3
1--9.9 Å20 Å20 Å2
2--21.86 Å20 Å2
3----11.96 Å2
Refine analyzeLuzzati coordinate error free: 0.55 Å / Luzzati sigma a free: 0.46 Å
Refinement stepCycle: LAST / Resolution: 2.9→19.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4055 0 57 28 4140
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.7
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.95
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 2.9→3.03 Å / Rfactor Rfree error: 0.052 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.383 55 6 %
Rwork0.371 862 -
obs-862 43.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION36ECDCA.PAR6ECDCA.TOP
X-RAY DIFFRACTION47ACDCA.PAR7ACDCA.TOP
Refinement
*PLUS
Lowest resolution: 15 Å / % reflection Rfree: 5 % / Rfactor Rfree: 0.29 / Rfactor Rwork: 0.254
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.011
X-RAY DIFFRACTIONc_angle_deg1.9
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.3
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.1

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