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- PDB-3rvf: FXR with SRC1 and GSK2034 -

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Basic information

Entry
Database: PDB / ID: 3rvf
TitleFXR with SRC1 and GSK2034
Components
  • Bile acid receptor
  • Nuclear receptor coactivator 1
KeywordsTRANSCRIPTION REGULATOR / nuclear receptor / alpha-helical sandwich / transcription factor / RXR / transcription co-factors / bile acid / farnesoid
Function / homology
Function and homology information


chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of ammonia assimilation cycle / regulation of low-density lipoprotein particle clearance / : / cellular response to bile acid / intracellular triglyceride homeostasis / urea metabolic process / negative regulation of interleukin-1 production / negative regulation of very-low-density lipoprotein particle remodeling ...chenodeoxycholic acid binding / positive regulation of phosphatidic acid biosynthetic process / positive regulation of ammonia assimilation cycle / regulation of low-density lipoprotein particle clearance / : / cellular response to bile acid / intracellular triglyceride homeostasis / urea metabolic process / negative regulation of interleukin-1 production / negative regulation of very-low-density lipoprotein particle remodeling / regulation of bile acid biosynthetic process / regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of monocyte chemotactic protein-1 production / toll-like receptor 9 signaling pathway / nuclear receptor-mediated bile acid signaling pathway / bile acid nuclear receptor activity / labyrinthine layer morphogenesis / bile acid binding / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / cellular response to fatty acid / cell-cell junction assembly / regulation of cholesterol metabolic process / negative regulation of interleukin-2 production / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / negative regulation of interleukin-6 production / bile acid and bile salt transport / male mating behavior / hypothalamus development / positive regulation of interleukin-17 production / negative regulation of type II interferon production / progesterone receptor signaling pathway / cellular response to Thyroglobulin triiodothyronine / Synthesis of bile acids and bile salts / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / negative regulation of tumor necrosis factor production / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / fatty acid homeostasis / positive regulation of insulin receptor signaling pathway / response to retinoic acid / protein-lysine-acetyltransferase activity / negative regulation of tumor necrosis factor-mediated signaling pathway / nuclear retinoid X receptor binding / estrous cycle / Recycling of bile acids and salts / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / histone acetyltransferase / lactation / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cellular response to hormone stimulus / estrogen receptor signaling pathway / intracellular receptor signaling pathway / peroxisome proliferator activated receptor signaling pathway / Regulation of lipid metabolism by PPARalpha / response to progesterone / positive regulation of adipose tissue development / cerebellum development / positive regulation of neuron differentiation / cholesterol homeostasis / BMAL1:CLOCK,NPAS2 activates circadian expression / regulation of cellular response to insulin stimulus / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / intracellular glucose homeostasis / nuclear estrogen receptor binding / nuclear receptor binding / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of canonical NF-kappaB signal transduction / transcription coregulator binding / hippocampus development / SUMOylation of intracellular receptors / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Heme signaling / male gonad development / PPARA activates gene expression / Cytoprotection by HMOX1 / Transcriptional activation of mitochondrial biogenesis / euchromatin / cerebral cortex development / Nuclear Receptor transcription pathway / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / mRNA transcription by RNA polymerase II / RNA polymerase II transcription regulator complex / nuclear receptor activity / response to estradiol / HATs acetylate histones / cellular response to lipopolysaccharide / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / transcription regulator complex / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / sequence-specific DNA binding / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / transcription coactivator activity
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 / Nuclear receptor coactivator, receptor-binding domain ...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 / Nuclear receptor coactivators bHLH domain / PAS domain / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / : / 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 / Double treble clef zinc finger, C4 type / 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-034 / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsWilliams, S.P. / Madauss, K.P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Conformationally constrained farnesoid X receptor (FXR) agonists: Alternative replacements of the stilbene.
Authors: Akwabi-Ameyaw, A. / Caravella, J.A. / Chen, L. / Creech, K.L. / Deaton, D.N. / Madauss, K.P. / Marr, H.B. / Miller, A.B. / Navas, F. / Parks, D.J. / Spearing, P.K. / Todd, D. / Williams, S.P. / Wisely, G.B.
History
DepositionMay 6, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2011Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2011Group: Database references
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software
Revision 1.3Feb 28, 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: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,3154
Polymers29,6982
Non-polymers6172
Water362
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1050 Å2
ΔGint-19 kcal/mol
Surface area11470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.331, 158.331, 158.331
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number196
Space group name H-MF23

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Components

#1: Protein Bile acid receptor / FXR / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group ...FXR / 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: 27048.021 Da / Num. of mol.: 1 / Fragment: ligand binding domain (UNP residues 257-486)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BAR, FXR, HRR1, NR1H4, RIP14 / Plasmid: pRSETA / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q96RI1
#2: Protein/peptide Nuclear receptor coactivator 1 / SRC1 / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / ...SRC1 / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal carcinoma antigen NY-REN-52 / Steroid receptor coactivator 1


Mass: 2650.017 Da / Num. of mol.: 1 / Fragment: UNP residues 741-761 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-034 / 5-(4-{[3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazol-4-yl]methoxy}phenyl)-1H-indole-2-carboxylic acid


Mass: 521.391 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H22Cl2N2O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 2.78 Å3/Da / Density % sol: 55.82 %
Crystal growTemperature: 298 K / Method: hanging drop / pH: 6.5
Details: 25% PEG3350, 0.2 M lithium sulfate, 0.1 M Bis-Tris, pH 6.5, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 15, 2005
RadiationMonochromator: CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. all: 6114 / Num. obs: 6084 / % possible obs: 99.6 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 11.2 % / Biso Wilson estimate: 40 Å2 / Rmerge(I) obs: 0.094 / Χ2: 0.952 / Net I/σ(I): 7.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
3.1-3.2111.20.4896020.9271100
3.21-3.3411.40.4086080.9061100
3.34-3.4911.30.2495980.9591100
3.49-3.6811.30.1926120.951100
3.68-3.9111.30.1315910.9871100
3.91-4.2111.30.0926180.9381100
4.21-4.6311.30.076070.9711100
4.63-5.311.20.0656110.9471100
5.3-6.6711.10.0696140.9231100
6.67-5010.60.0336231.014196

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.1→20.61 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.852 / WRfactor Rfree: 0.2642 / WRfactor Rwork: 0.2018 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7826 / SU B: 18.085 / SU ML: 0.315 / SU Rfree: 0.1124 / Isotropic thermal model: ISOTROPIC / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.112 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2903 448 7.4 %RANDOM
Rwork0.2225 ---
all0.2274 6114 --
obs0.2274 6068 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 140.96 Å2 / Biso mean: 59.8653 Å2 / Biso min: 25.01 Å2
Refinement stepCycle: LAST / Resolution: 3.1→20.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1846 0 41 2 1889
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0211930
X-RAY DIFFRACTIONr_bond_other_d0.0020.021229
X-RAY DIFFRACTIONr_angle_refined_deg1.0841.9862632
X-RAY DIFFRACTIONr_angle_other_deg1.00933008
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4485237
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.84524.3982
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.84315304
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.488158
X-RAY DIFFRACTIONr_chiral_restr0.0540.2304
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212136
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02382
LS refinement shellResolution: 3.098→3.177 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.252 40 -
Rwork0.259 389 -
all-429 -
obs--98.17 %

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