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- PDB-3p88: FXR bound to isoquinolinecarboxylic acid -

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Basic information

Entry
Database: PDB / ID: 3p88
TitleFXR bound to isoquinolinecarboxylic acid
Components
  • Farnesoid X receptor
  • Nuclear receptor coactivator 1
KeywordsTRANSCRIPTION/INHIBITOR / nuclear recptor FXR / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


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 ...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 / 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 / nitrogen catabolite activation of transcription from RNA polymerase II promoter / labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / bile acid binding / cell-cell junction assembly / positive regulation of female receptivity / bile acid signaling pathway / cellular response to fatty acid / negative regulation of interleukin-2 production / regulation of cholesterol metabolic process / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of interleukin-17 production / intracellular glucose homeostasis / 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 / cellular response to Thyroglobulin triiodothyronine / negative regulation of tumor necrosis factor-mediated signaling pathway / estrous cycle / Synthesis of bile acids and bile salts / 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 / response to retinoic acid / negative regulation of canonical NF-kappaB signal transduction / histone acetyltransferase activity / Recycling of bile acids and salts / histone acetyltransferase / Notch signaling pathway / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / regulation of cellular response to insulin stimulus / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / transcription coregulator binding / response to progesterone / cholesterol homeostasis / hippocampus development / nuclear estrogen receptor binding / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Heme signaling / SUMOylation of intracellular receptors / euchromatin / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / negative regulation of inflammatory response / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / nuclear receptor activity / male gonad development / Circadian Clock / response to estradiol / HATs acetylate histones / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to lipopolysaccharide / Estrogen-dependent gene expression / transcription regulator complex / sequence-specific DNA binding / transcription by RNA polymerase II / 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 / 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 / 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-P88 / Nuclear receptor coactivator / Farnesoid X receptor / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsMadauss, K.P. / Williams, S.P. / Deaton, D.N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene.
Authors: Bass, J.Y. / Caravella, J.A. / Chen, L. / Creech, K.L. / Deaton, D.N. / Madauss, K.P. / Marr, H.B. / McFadyen, R.B. / Miller, A.B. / Mills, W.Y. / Navas, F. / Parks, D.J. / Smalley, T.L. / ...Authors: Bass, J.Y. / Caravella, J.A. / Chen, L. / Creech, K.L. / Deaton, D.N. / Madauss, K.P. / Marr, H.B. / McFadyen, R.B. / Miller, A.B. / Mills, W.Y. / Navas, F. / Parks, D.J. / Smalley, T.L. / Spearing, P.K. / Todd, D. / Williams, S.P. / Wisely, G.B.
History
DepositionOct 13, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.2Feb 21, 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

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Assembly

Deposited unit
A: Farnesoid X receptor
B: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,8764
Polymers28,2872
Non-polymers5892
Water23413
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1090 Å2
ΔGint-20 kcal/mol
Surface area11540 Å2
MethodPISA
2
A: Farnesoid X receptor
B: Nuclear receptor coactivator 1
hetero molecules
x 12


Theoretical massNumber of molelcules
Total (without water)346,51248
Polymers339,44824
Non-polymers7,06424
Water43224
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_566z,-x+1,-y+11
crystal symmetry operation12_665-y+1,-z+1,x1
crystal symmetry operation16_556x,-y+1/2,-z+3/21
crystal symmetry operation17_545z,x-1/2,y+1/21
crystal symmetry operation22_646-y+1,z-1/2,-x+3/21
crystal symmetry operation27_656-x+3/2,y,-z+3/21
crystal symmetry operation31_665-z+3/2,-x+1,y+1/21
crystal symmetry operation35_566y+1/2,-z+1,-x+3/21
crystal symmetry operation38_655-x+3/2,-y+1/2,z1
crystal symmetry operation44_646-z+3/2,x-1/2,-y+11
crystal symmetry operation45_545y+1/2,z-1/2,x1
Buried area32040 Å2
ΔGint-424 kcal/mol
Surface area119600 Å2
MethodPISA
3
A: Farnesoid X receptor
B: Nuclear receptor coactivator 1
hetero molecules

A: Farnesoid X receptor
B: Nuclear receptor coactivator 1
hetero molecules

A: Farnesoid X receptor
B: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,62812
Polymers84,8626
Non-polymers1,7666
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation35_566y+1/2,-z+1,-x+3/21
crystal symmetry operation44_646-z+3/2,x-1/2,-y+11
Buried area5440 Å2
ΔGint-85 kcal/mol
Surface area32470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)158.537, 158.537, 158.537
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 Farnesoid X receptor / Nuclear receptor subfamily 1 / group H / member 4 / isoform CRA_a


Mass: 26870.686 Da / Num. of mol.: 1 / Fragment: unp residues 244-472 / Mutation: C432E, C466E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: hCG_20893, NR1H4 / Production host: Escherichia coli (E. coli) / References: UniProt: B6ZGS9, UniProt: Q96RI1*PLUS
#2: Protein/peptide Nuclear receptor coactivator 1


Mass: 1416.645 Da / Num. of mol.: 1 / Fragment: unp residues 745-755
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BHLHE74, NCOA1, SRC1 / Production host: Escherichia coli (E. coli) / References: UniProt: A8K1V4, UniProt: Q15788*PLUS
#3: Chemical ChemComp-P88 / 7-(4-{[3-(2,6-dimethylphenyl)-5-(1-methylethyl)isoxazol-4-yl]methoxy}phenyl)isoquinoline-3-carboxylic acid


Mass: 492.565 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H28N2O4
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 3.09 Å3/Da / Density % sol: 60.15 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: peg3350 22%, Hepes, 0.2 M Li2SO4, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 5, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 7449 / % possible obs: 99.8 % / Redundancy: 10.5 % / Rmerge(I) obs: 0.067 / Χ2: 1.151 / Net I/σ(I): 12.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.9-36.40.4847360.951198.1
3-3.129.60.3487391.0191100
3.12-3.27110.2667201.11100
3.27-3.4411.20.1847401.1491100
3.44-3.6511.30.1317341.2031100
3.65-3.9411.30.0867421.2241100
3.94-4.3311.20.0577491.1281100
4.33-4.9611.20.0467481.1911100
4.96-6.2411.10.0487551.1511100
6.24-5010.50.0327861.274199.9

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
StructureStudiodata collection
DENZOdata reduction
HKL-2000data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.95→47.78 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.895 / WRfactor Rfree: 0.2821 / WRfactor Rwork: 0.2343 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7332 / SU B: 52.443 / SU ML: 0.417 / SU R Cruickshank DPI: 0.4177 / SU Rfree: 0.4887 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.476 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2889 510 7.2 %RANDOM
Rwork0.2375 ---
obs0.2413 7055 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 72.36 Å2 / Biso mean: 54.7461 Å2 / Biso min: 21.42 Å2
Refinement stepCycle: LAST / Resolution: 2.95→47.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1885 0 42 13 1940
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0221969
X-RAY DIFFRACTIONr_bond_other_d0.0010.021254
X-RAY DIFFRACTIONr_angle_refined_deg0.8321.9852684
X-RAY DIFFRACTIONr_angle_other_deg0.76333072
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.1375238
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.30824.83591
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.16115318
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.268159
X-RAY DIFFRACTIONr_chiral_restr0.040.2306
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212185
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02385
X-RAY DIFFRACTIONr_mcbond_it0.1541.51204
X-RAY DIFFRACTIONr_mcbond_other0.0171.5474
X-RAY DIFFRACTIONr_mcangle_it0.29421931
X-RAY DIFFRACTIONr_scbond_it0.3373765
X-RAY DIFFRACTIONr_scangle_it0.6144.5753
LS refinement shellResolution: 2.95→3.026 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.478 31 -
Rwork0.333 460 -
all-491 -
obs--100 %

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