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- PDB-4oiv: Structural basis for small molecule NDB as a selective antagonist... -

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Basic information

Entry
Database: PDB / ID: 4oiv
TitleStructural basis for small molecule NDB as a selective antagonist of FXR
ComponentsBile acid receptor
KeywordsNUCLEAR PROTEIN RECEPTOR / bile acid sensor / nuclear
Function / homology
Function and homology information


regulation of urea metabolic process / 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 ...regulation of urea metabolic process / 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 / nuclear receptor-mediated bile acid signaling pathway / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / : / toll-like receptor 9 signaling pathway / negative regulation of monocyte chemotactic protein-1 production / bile acid nuclear receptor activity / bile acid metabolic process / cell-cell junction assembly / bile acid binding / cellular response to fatty acid / regulation of cholesterol metabolic process / negative regulation of interleukin-2 production / 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 / 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 / positive regulation of insulin receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / 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 / SUMOylation of intracellular receptors / euchromatin / PPARA activates gene expression / negative regulation of inflammatory response / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / 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 / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / innate immune response / regulation of DNA-templated transcription / chromatin / 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 / 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. ...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-XX9 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsXu, X. / Chen, L. / Hu, L. / Shen, X.
CitationJournal: J.Biol.Chem. / Year: 2015
Title: Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXR ...Title: Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXR alpha ) in Stabilizing the Homodimerization of the Receptor.
Authors: Xu, X. / Xu, X. / Liu, P. / Zhu, Z.Y. / Chen, J. / Fu, H.A. / Chen, L.L. / Hu, L.H. / Shen, X.
History
DepositionJan 20, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Mar 25, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 19, 2015Group: Database references
Revision 1.2Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)53,9684
Polymers53,0252
Non-polymers9432
Water3,207178
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3640 Å2
ΔGint-29 kcal/mol
Surface area20630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.625, 84.625, 172.234
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Bile acid receptor / FXR-LBD / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 ...FXR-LBD / 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: 26512.381 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 258-483 / Mutation: C436E, C470E
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: Chemical ChemComp-XX9 / N-benzyl-N-(3-tert-butyl-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino)benzamide


Mass: 471.419 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28Cl2N2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / 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: 2.91 Å3/Da / Density % sol: 57.7 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.9
Details: 16-26% polyethylene glycol 2000 MME, 0.2M NaCl, 0.1M MES, pH 5.9, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97915 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 1.7→38.38 Å / Num. obs: 68951 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3
Reflection shellResolution: 1.7→1.73 Å

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASESphasing
REFMAC5.5.0110refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3FLI

3fli


Resolution: 1.7→38.38 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.928 / SU B: 2.172 / SU ML: 0.071 / Cross valid method: THROUGHOUT / ESU R: 0.101 / ESU R Free: 0.103 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23946 3383 5.1 %RANDOM
Rwork0.20615 ---
obs0.20783 63144 96.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.57 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20 Å2
2--0.01 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 1.7→38.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3523 0 64 178 3765
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0270.0223663
X-RAY DIFFRACTIONr_angle_refined_deg2.2961.9864954
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5925423
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.52125.11182
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.415680
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.9061517
X-RAY DIFFRACTIONr_chiral_restr0.3740.2548
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212749
X-RAY DIFFRACTIONr_mcbond_it1.4231.52142
X-RAY DIFFRACTIONr_mcangle_it2.62523477
X-RAY DIFFRACTIONr_scbond_it4.33631521
X-RAY DIFFRACTIONr_scangle_it6.824.51477
LS refinement shellResolution: 1.704→1.748 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.299 163 -
Rwork0.265 3017 -
obs--63.97 %

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