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- PDB-3fxv: Identification of an N-oxide pyridine GW4064 analogue as a potent... -

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Basic information

Entry
Database: PDB / ID: 3fxv
TitleIdentification of an N-oxide pyridine GW4064 analogue as a potent FXR agonist
Components
  • 12-meric peptide from Nuclear receptor coactivator 1
  • NR1H4 protein
Keywordshormone receptor / NUCLEAR RECEPTOR / CHOLESTEROL / BILE ACID / DNA-binding / Metal-binding / Nucleus / Receptor / Transcription / Transcription regulation / Zinc / Zinc-finger / Activator / Acyltransferase / Alternative splicing / Chromosomal rearrangement / Phosphoprotein / Polymorphism / Proto-oncogene / Transferase / Ubl conjugation
Function / homology
Function and homology information


interleukin-17 production / : / negative regulation of tumor necrosis factor production => GO:0032720 / euchromatin => GO:0000791 / regulation of urea metabolic process / nuclear receptor-mediated bile acid signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle ...interleukin-17 production / : / negative regulation of tumor necrosis factor production => GO:0032720 / euchromatin => GO:0000791 / regulation of urea metabolic process / nuclear receptor-mediated bile acid signaling pathway / chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of glutamate metabolic process / positive regulation of ammonia assimilation cycle / : / 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 / chromatin => GO:0000785 / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / : / toll-like receptor 9 signaling pathway / intracellular receptor signaling pathway / negative regulation of monocyte chemotactic protein-1 production / bile acid metabolic process / lipid homeostasis / nitrogen catabolite activation of transcription from RNA polymerase II promoter / bile acid and bile salt transport / labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / cell-cell junction assembly / bile acid binding / positive regulation of female receptivity / bile acid signaling pathway / cellular response to fatty acid / toll-like receptor 4 signaling pathway / regulation of cholesterol metabolic process / negative regulation of NF-kappaB transcription factor activity / hypothalamus development / negative regulation of interleukin-2 production / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / intracellular glucose homeostasis / positive regulation of interleukin-17 production / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of interleukin-6 production / transcription factor binding / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / negative regulation of tumor necrosis factor production / negative regulation of type II interferon production / cellular response to Thyroglobulin triiodothyronine / estrous cycle / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor-mediated signaling pathway / fatty acid homeostasis / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / regulation of cellular response to insulin stimulus / response to retinoic acid / positive regulation of insulin receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / histone acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / Notch signaling pathway / RORA activates gene expression / transcription coregulator binding / positive regulation of neuron differentiation / lactation / Regulation of lipid metabolism by PPARalpha / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / SUMOylation of intracellular receptors / cholesterol homeostasis / mRNA transcription by RNA polymerase II / response to progesterone / nuclear receptor binding / hippocampus development / nuclear estrogen receptor binding / lipid metabolic process / transcription initiation at RNA polymerase II promoter / RNA polymerase II transcription regulatory region sequence-specific DNA binding / PPARA activates gene expression / negative regulation of inflammatory response / Heme signaling / Nuclear Receptor transcription pathway / euchromatin / Transcriptional activation of mitochondrial biogenesis / Transcriptional regulation of white adipocyte differentiation / Cytoprotection by HMOX1 / RNA polymerase II transcription regulator complex
Similarity search - Function
Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 1 / : / 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 ...Bile acid receptor, ligand binding domain / Thyroid hormone receptor / Nuclear receptor coactivator 1 / : / 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 / Retinoid X Receptor / Retinoid X Receptor / PAS domain superfamily / 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 / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Ligand-binding domain of nuclear hormone receptor / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-643 / Bile acid receptor / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsFeng, S. / Yang, M. / He, Y. / Chen, L. / Zhang, Z. / Wang, Z. / Hong, D. / Richter, H. / Benson, G.M. / Bleicher, K. ...Feng, S. / Yang, M. / He, Y. / Chen, L. / Zhang, Z. / Wang, Z. / Hong, D. / Richter, H. / Benson, G.M. / Bleicher, K. / Grether, U. / Martin, R. / Plancher, J.-M. / Kuhn, B. / Rudolph, M.G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist
Authors: Feng, S. / Yang, M. / Zhang, Z. / Wang, Z. / Hong, D. / Richter, H. / Benson, G.M. / Bleicher, K. / Grether, U. / Martin, R.E. / Plancher, J.-M. / Kuhn, B. / Rudolph, M.G. / Chen, L.
History
DepositionJan 21, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Apr 14, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Nov 10, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_nonpoly / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NR1H4 protein
B: 12-meric peptide from Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,3123
Polymers28,7612
Non-polymers5501
Water1,06359
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1120 Å2
ΔGint-5 kcal/mol
Surface area12100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.796, 94.796, 48.274
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#1: Protein NR1H4 protein / FXR / Nuclear receptor subfamily 1 / group H / member 4 / isoform CRA_b


Mass: 27100.191 Da / Num. of mol.: 1 / Fragment: ligand binding domain, residues 248-475 / Mutation: E281A, E354A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1H4, hCG_20893 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: A1L4K5, UniProt: Q96RI1*PLUS
#2: Protein/peptide 12-meric peptide from Nuclear receptor coactivator 1 / SRC-1 / NCoA-1 / Steroid receptor coactivator 1 / RIP160 / Protein Hin-2 / Renal carcinoma antigen NY-REN-52


Mass: 1660.912 Da / Num. of mol.: 1 / Fragment: residues 744-756 / Source method: obtained synthetically / Details: This sequence occurs naturally in humans. / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788
#3: Chemical ChemComp-643 / 6-(4-{[3-(3,5-dichloropyridin-4-yl)-5-(1-methylethyl)isoxazol-4-yl]methoxy}-2-methylphenyl)-1-methyl-1H-indole-3-carbox ylic acid / 6-{4-[3-(3,5-Dichloro-pyridin-4-yl)-5-isopropyl-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-1H-indole-3-carboxylic acid


Mass: 550.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H25Cl2N3O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / 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: 2.18 Å3/Da / Density % sol: 43.5 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jan 21, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.26→48.27 Å / Num. all: 11724 / Num. obs: 11644 / % possible obs: 99.3 % / Observed criterion σ(I): 0 / Redundancy: 4.14 % / Biso Wilson estimate: 49.457 Å2 / Rsym value: 0.0482 / Net I/σ(I): 16.46
Reflection shellResolution: 2.26→2.31 Å / Redundancy: 3.35 % / Mean I/σ(I) obs: 2.5 / Num. unique all: 522 / Rsym value: 0.3952 / % possible all: 95.6

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Processing

Software
NameVersionClassification
COMOphasing
BUSTER-TNT2.1.1refinement
HKL-2000data reduction
SADABSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished FXR model

Resolution: 2.26→41.61 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2421 575 4.94 %RANDOM
Rwork0.1883 ---
obs0.191 11634 99.11 %-
Displacement parametersBiso mean: 48.65 Å2
Baniso -1Baniso -2Baniso -3
1-1.46070682 Å20 Å20 Å2
2--1.46070682 Å20 Å2
3----2.92141364 Å2
Refinement stepCycle: LAST / Resolution: 2.26→41.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1929 0 38 59 2026
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.00820102
X-RAY DIFFRACTIONt_angle_deg0.85727102
X-RAY DIFFRACTIONt_dihedral_angle_d23.3114180
X-RAY DIFFRACTIONt_trig_c_planes0.006572
X-RAY DIFFRACTIONt_gen_planes0.0112805
X-RAY DIFFRACTIONt_it1.518201020
X-RAY DIFFRACTIONt_nbd0.067235
LS refinement shellResolution: 2.26→2.4 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.3278 92 5.08 %
Rwork0.2571 1718 -
all0.2606 1810 -
obs--99.11 %

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