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- PDB-1osv: STRUCTURAL BASIS FOR BILE ACID BINDING AND ACTIVATION OF THE NUCL... -

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Basic information

Entry
Database: PDB / ID: 1osv
TitleSTRUCTURAL BASIS FOR BILE ACID BINDING AND ACTIVATION OF THE NUCLEAR RECEPTOR FXR
Components
  • Bile acid receptor
  • Nuclear receptor coactivator 2
KeywordsDNA BINDING PROTEIN / LBD / bile acid / coactivator / nuclear receptor
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 / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol ...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 / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts / regulation of carbohydrate metabolic process / positive regulation of glucocorticoid receptor signaling pathway / regulation of lipid storage / Endogenous sterols / HATs acetylate histones / 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 / Regulation of lipid metabolism by PPARalpha / Nuclear Receptor transcription pathway / negative regulation of very-low-density lipoprotein particle remodeling / Cytoprotection by HMOX1 / negative regulation of interleukin-1 production / leukocyte migration involved in inflammatory response / nuclear glucocorticoid receptor binding / Estrogen-dependent gene expression / regulation of insulin secretion involved in cellular response to glucose stimulus / cellular response to organonitrogen compound / toll-like receptor 9 signaling pathway / triglyceride homeostasis / nuclear retinoic acid receptor binding / 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 / positive regulation of female receptivity / bile acid binding / bile acid signaling pathway / nuclear thyroid hormone receptor binding / negative regulation of interleukin-2 production / cellular response to fatty acid / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / positive regulation of interleukin-17 production / locomotor rhythm / positive regulation of insulin secretion involved in cellular response to glucose stimulus / intracellular glucose homeostasis / negative regulation of interleukin-6 production / aryl hydrocarbon receptor binding / negative regulation of type II interferon production / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / negative regulation of tumor necrosis factor production / regulation of glucose metabolic process / negative regulation of tumor necrosis factor-mediated signaling pathway / fatty acid homeostasis / response to glucose / DNA polymerase binding / nuclear retinoid X receptor binding / negative regulation of canonical NF-kappaB signal transduction / positive regulation of insulin receptor signaling pathway / regulation of cellular response to insulin stimulus / Notch signaling pathway / cellular response to hormone stimulus / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / response to nutrient levels / cholesterol homeostasis / nuclear receptor coactivator activity / response to progesterone / liver regeneration / nuclear estrogen receptor binding / transcription coregulator binding / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / circadian regulation of gene expression / euchromatin / mRNA transcription by RNA polymerase II / response to organic cyclic compound / negative regulation of inflammatory response / circadian rhythm / RNA polymerase II transcription regulator complex / response to estrogen / nuclear receptor activity
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Nuclear receptor coactivator, interlocking / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / 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 / Nuclear receptor coactivator 2 / Bile acid receptor
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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 20, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 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_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

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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: Nuclear receptor coactivator 2
D: Nuclear receptor coactivator 2
E: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,9377
Polymers58,0965
Non-polymers8412
Water2,738152
1
A: Bile acid receptor
C: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,7363
Polymers28,3162
Non-polymers4211
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2020 Å2
ΔGint-9 kcal/mol
Surface area12440 Å2
MethodPISA
2
B: Bile acid receptor
D: Nuclear receptor coactivator 2
E: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2014
Polymers29,7803
Non-polymers4211
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3230 Å2
ΔGint-11 kcal/mol
Surface area12790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.970, 108.518, 69.464
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
DetailsThe biological assembly is one of the two subunits in the asymmetric unit - A or B

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Components

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


Mass: 26850.891 Da / Num. of mol.: 2 / Fragment: ligand binding domain (FXR-LBD)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Plasmid: pET16b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q62735
#2: Protein/peptide Nuclear receptor coactivator 2 / / NCoA-2 / Transcription intermediary factor 2 / Glucocorticoid receptor-interacting protein 1 / GRIP-1


Mass: 1464.664 Da / Num. of mol.: 3 / Fragment: Residues (741-752) / Source method: obtained synthetically
Details: The coactivator peptide was synthesized. The sequence of the GRIP is naturally found in Rattus Norvegicus (Norway Rat).
References: UniProt: Q61026
#3: Chemical ChemComp-CHC / 6-ETHYL-CHENODEOXYCHOLIC ACID / Obeticholic acid


Mass: 420.625 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H44O4 / Comment: medication*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 152 / 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: 3.12 Å3/Da / Density % sol: 60.31 %
Crystal growTemperature: 283 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: PEG 8000,Ethylene Glycol, PIPES , pH 6.4, VAPOR DIFFUSION, HANGING DROP, temperature 283K
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: APS / Beamline: 19-BM / Wavelength: 1.0332 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 19, 2002
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.5→24.3 Å / Num. all: 26840 / Num. obs: 24908 / Observed criterion σ(F): 3 / Observed criterion σ(I): 3 / Redundancy: 4 % / Biso Wilson estimate: 44.2 Å2 / Rsym value: 0.044 / Net I/σ(I): 19.61
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 3.04 / Rsym value: 0.282 / % possible all: 77.2
Reflection
*PLUS
Lowest resolution: 24.3 Å / Num. obs: 24427 / % possible obs: 92.8 % / Num. measured all: 99829 / Rmerge(I) obs: 0.044
Reflection shell
*PLUS
% possible obs: 77.2 % / Rmerge(I) obs: 0.282

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→19.88 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1628529.25 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.276 1681 6.9 %RANDOM
Rwork0.242 ---
obs0.242 24238 91.4 %-
all-24427 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.8465 Å2 / ksol: 0.320304 e/Å3
Displacement parametersBiso mean: 55.2 Å2
Baniso -1Baniso -2Baniso -3
1--6.77 Å20 Å20 Å2
2--9.98 Å20 Å2
3----3.22 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.43 Å0.37 Å
Luzzati d res low-20 Å
Luzzati sigma a0.39 Å0.33 Å
Refinement stepCycle: LAST / Resolution: 2.5→19.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4053 0 60 152 4265
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
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_deg1.4
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.6
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.82
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it6.121.5
X-RAY DIFFRACTIONc_mcangle_it8.682
X-RAY DIFFRACTIONc_scbond_it8.082
X-RAY DIFFRACTIONc_scangle_it10.342.5
LS refinement shellResolution: 2.5→2.59 Å / Rfactor Rfree error: 0.034 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.388 128 6.4 %
Rwork0.334 1861 -
obs--76.1 %
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 DIFFRACTION46ECDCA2.PAR6ECDCA2.TOP
Refinement
*PLUS
Lowest resolution: 24.3 Å / % reflection Rfree: 5 % / Rfactor Rfree: 0.281 / Rfactor Rwork: 0.251
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg19.5
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.93

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