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- PDB-5iaw: Novel natural FXR modulator with a unique binding mode -

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Basic information

Entry
Database: PDB / ID: 5iaw
TitleNovel natural FXR modulator with a unique binding mode
Components
  • Bile acid receptor
  • Peptide from Nuclear receptor coactivator 2
KeywordsTRANSCRIPTION / NUCLEAR PROTEIN RECEPTOR
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 / bile acid binding / cell-cell junction assembly / bile acid signaling pathway / negative regulation of interleukin-2 production / cellular response to fatty acid / regulation of cholesterol metabolic process / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / positive regulation of interleukin-17 production / intracellular glucose homeostasis / locomotor rhythm / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of interleukin-6 production / aryl hydrocarbon receptor binding / regulation of lipid metabolic process / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / 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 / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / cellular response to hormone stimulus / Notch signaling pathway / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / Regulation of lipid metabolism by PPARalpha / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / response to progesterone / cholesterol homeostasis / transcription coregulator binding / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / circadian regulation of gene expression / Heme signaling / SUMOylation of intracellular receptors / euchromatin / 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 / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / Circadian Clock / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / cellular response to lipopolysaccharide / transcription regulator complex / sequence-specific DNA binding / transcription by RNA polymerase II / transcription coactivator activity / cell differentiation / nuclear body / receptor complex / protein dimerization activity / 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 / protein domain specific binding / innate immune response / chromatin binding
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 / Nuclear receptor coactivator, interlocking / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / 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
Chem-T73 / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.58 Å
AuthorsLu, Y. / Li, Y.
CitationJournal: Chembiochem / Year: 2017
Title: A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co-regulator Assembly
Authors: Zheng, W. / Lu, Y. / Lin, S. / Wang, R. / Qiu, L. / Zhu, Y. / Yao, B. / Guo, F. / Jin, S. / Jin, L. / Li, Y.
History
DepositionFeb 22, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 8, 2017Provider: repository / Type: Initial release
Revision 1.1May 3, 2017Group: Database references
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_low

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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: Peptide from Nuclear receptor coactivator 2
D: Peptide from Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,6117
Polymers55,7884
Non-polymers8233
Water63135
1
A: Bile acid receptor
C: Peptide from Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,4434
Polymers27,8942
Non-polymers5492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1090 Å2
ΔGint-6 kcal/mol
Surface area12190 Å2
MethodPISA
2
B: Bile acid receptor
D: Peptide from Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1683
Polymers27,8942
Non-polymers2741
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint-4 kcal/mol
Surface area11960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.748, 34.951, 144.107
Angle α, β, γ (deg.)90.000, 90.740, 90.000
Int Tables number3
Space group name H-MP121

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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: 26673.674 Da / Num. of mol.: 2 / Fragment: UNP residues 259-486
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, BAR, FXR, HRR1, RIP14 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q96RI1
#2: Protein/peptide Peptide from Nuclear receptor coactivator 2 /


Mass: 1220.462 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: A0A0B6XJZ8, UniProt: Q15596*PLUS
#3: Chemical ChemComp-T73 / (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-hydroxybenzoate


Mass: 274.355 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C17H22O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 35 / 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: 2.47 Å3/Da / Density % sol: 50.3 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.2M sodium chloride, 0.1M HEPES pH 7.5, 25% w/v polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 293.15 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 1.005 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 9, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.005 Å / Relative weight: 1
ReflectionResolution: 2.58→50 Å / Num. all: 17753 / Num. obs: 16539 / % possible obs: 97.5 % / Redundancy: 4.4 % / Rmerge(I) obs: 0.079 / Net I/av σ(I): 16.481 / Net I/σ(I): 10.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.58-2.614.30.278196.4
2.61-2.674.40.269196.6
2.67-2.744.30.224195.9
2.74-2.814.40.201196.2
2.81-2.894.30.161195.5
2.89-2.994.40.146197.2
2.99-3.094.30.12196.3
3.09-3.224.30.096196
3.22-3.364.30.082197.9
3.36-3.544.30.074197.4
3.54-3.764.20.069199
3.76-4.054.30.06199.7
4.05-4.464.40.0521100
4.46-5.14.60.052199.8
5.1-6.434.70.047199.8
6.43-504.50.035199.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
Cootmodel building
PHASERphasing
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.58→36.338 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.896 / SU B: 9.75 / SU ML: 0.213 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.385 / ESU R Free: 0.324 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2491 818 4.7 %RANDOM
Rwork0.1946 ---
obs0.1972 16539 97.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 88.54 Å2 / Biso mean: 36.114 Å2 / Biso min: 13.38 Å2
Baniso -1Baniso -2Baniso -3
1--0.71 Å2-0 Å20.62 Å2
2---0.39 Å20 Å2
3---1.08 Å2
Refinement stepCycle: final / Resolution: 2.58→36.338 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3905 0 60 35 4000
Biso mean--31.65 30.01 -
Num. residues----475
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0194048
X-RAY DIFFRACTIONr_bond_other_d0.0010.023946
X-RAY DIFFRACTIONr_angle_refined_deg2.0241.9915480
X-RAY DIFFRACTIONr_angle_other_deg0.90839099
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3015471
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.64224.898196
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.51615760
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4311520
X-RAY DIFFRACTIONr_chiral_restr0.0990.2618
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0214435
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02909
X-RAY DIFFRACTIONr_mcbond_it2.7673.3291896
X-RAY DIFFRACTIONr_mcbond_other2.7663.3291897
X-RAY DIFFRACTIONr_mcangle_it4.2734.992363
LS refinement shellResolution: 2.58→2.647 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.29 61 -
Rwork0.234 1179 -
all-1240 -
obs--96.8 %

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