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- PDB-3p89: FXR bound to a quinolinecarboxylic acid -

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Basic information

Entry
Database: PDB / ID: 3p89
TitleFXR bound to a quinolinecarboxylic acid
Components
  • Farnesoid X receptor
  • Nuclear receptor coactivator 1
KeywordsTRANSCRIPTION/INHIBITOR / nuclear receptor FXR / TRANSCRIPTION-INHIBITOR complex
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 / cellular response to fatty acid / positive regulation of female receptivity / cell-cell junction assembly / regulation of cholesterol metabolic process / triglyceride homeostasis / negative regulation of interleukin-2 production / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / 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 / negative regulation of interleukin-6 production / Synthesis of bile acids and bile salts / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / 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 / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Recycling of bile acids and salts / histone acetyltransferase / 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 / positive regulation of adipose tissue development / response to progesterone / lactation / BMAL1:CLOCK,NPAS2 activates circadian expression / regulation of cellular response to insulin stimulus / positive regulation of neuron differentiation / 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 / cerebellum development / cholesterol homeostasis / intracellular glucose homeostasis / nuclear estrogen receptor binding / nuclear receptor binding / positive regulation of insulin secretion involved in cellular response to glucose stimulus / transcription coregulator binding / negative regulation of canonical NF-kappaB signal transduction / hippocampus development / SUMOylation of intracellular receptors / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Heme signaling / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / Cytoprotection by HMOX1 / euchromatin / cerebral cortex development / Nuclear Receptor transcription pathway / male gonad development / Transcriptional regulation of white adipocyte differentiation / negative regulation of inflammatory response / mRNA transcription by RNA polymerase II / nuclear receptor activity / RNA polymerase II transcription regulator complex / 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 / DNA-binding transcription activator activity, RNA polymerase II-specific / transcription regulator complex / Estrogen-dependent gene expression / sequence-specific DNA binding / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation
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-89P / Nuclear receptor coactivator / Bile acid receptor / Nuclear receptor coactivator 1 / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 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
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

Downloads & links

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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)28,9014
Polymers28,2712
Non-polymers6292
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint-15 kcal/mol
Surface area11500 Å2
MethodPISA
2
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)86,70312
Polymers84,8146
Non-polymers1,8886
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation23_566y,-z+3/2,-x+3/21
crystal symmetry operation32_656-z+3/2,x,-y+3/21
Buried area5780 Å2
ΔGint-76 kcal/mol
Surface area32270 Å2
MethodPISA
3
A: Farnesoid X receptor
B: Nuclear receptor coactivator 1
hetero molecules
x 12


Theoretical massNumber of molelcules
Total (without water)346,81048
Polymers339,25724
Non-polymers7,55424
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_775-x+2,-y+2,z1
crystal symmetry operation3_756-x+2,y,-z+11
crystal symmetry operation4_576x,-y+2,-z+11
crystal symmetry operation21_554y,z+1/2,x-1/21
crystal symmetry operation22_756-y+2,z+1/2,-x+3/21
crystal symmetry operation23_566y,-z+3/2,-x+3/21
crystal symmetry operation24_764-y+2,-z+3/2,x-1/21
crystal symmetry operation29_554z+1/2,x,y-1/21
crystal symmetry operation30_576z+1/2,-x+2,-y+3/21
crystal symmetry operation31_674-z+3/2,-x+2,y-1/21
crystal symmetry operation32_656-z+3/2,x,-y+3/21
Buried area34550 Å2
ΔGint-372 kcal/mol
Surface area117650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)159.911, 159.911, 159.911
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 26854.730 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 / Steroid receptor coactivator 1 / SRC-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, histone acetyltransferase
#3: Chemical ChemComp-89P / 6-(4-{[3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazol-4-yl]methoxy}phenyl)quinoline-2-carboxylic acid


Mass: 533.402 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H22Cl2N2O4
#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.: 76 / 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: 3.23 Å3/Da / Density % sol: 61.9 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: peg3350 20%, .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, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 15143 / % possible obs: 100 % / Redundancy: 11.3 % / Rmerge(I) obs: 0.058 / Χ2: 1.12 / Net I/σ(I): 13.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.3-2.3811.40.48914660.8681100
2.38-2.4811.40.36215060.8541100
2.48-2.5911.40.24615090.8371100
2.59-2.7311.40.18714960.9091100
2.73-2.911.40.13215140.8851100
2.9-3.1211.40.09115130.9781100
3.12-3.4411.40.06615211.2161100
3.44-3.9311.30.05115071.5131100
3.93-4.9511.30.03915371.5391100
4.95-5010.70.03615741.6199.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
StructureStudiodata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→48.22 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.921 / WRfactor Rfree: 0.2692 / WRfactor Rwork: 0.2472 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8015 / SU B: 14.594 / SU ML: 0.172 / SU R Cruickshank DPI: 0.3376 / SU Rfree: 0.2408 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.225 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2547 1110 7.3 %RANDOM
Rwork0.2254 ---
obs0.2276 15137 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: 65.2 Å2 / Biso mean: 54.898 Å2 / Biso min: 18.03 Å2
Refinement stepCycle: LAST / Resolution: 2.3→48.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1849 0 42 76 1967
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0221933
X-RAY DIFFRACTIONr_bond_other_d0.0010.021249
X-RAY DIFFRACTIONr_angle_refined_deg0.8931.9852627
X-RAY DIFFRACTIONr_angle_other_deg0.80933052
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6255231
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.60724.83591
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.2715319
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.634159
X-RAY DIFFRACTIONr_chiral_restr0.0480.2296
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022137
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02383
X-RAY DIFFRACTIONr_mcbond_it0.2971.51172
X-RAY DIFFRACTIONr_mcbond_other0.0431.5466
X-RAY DIFFRACTIONr_mcangle_it0.56621875
X-RAY DIFFRACTIONr_scbond_it0.7893761
X-RAY DIFFRACTIONr_scangle_it1.314.5752
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.358 88 -
Rwork0.292 1009 -
all-1097 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.0699-0.3533-0.59742.4051-0.2122.2173-0.12470.00180.130.20510.14140.48620.0085-0.467-0.01670.04660.00390.03990.1110.00840.125126.9422158.7413105.0297
27.0304-1.8327-2.07883.2097-1.21629.2303-0.2598-0.01090.5412-0.02430.15940.4439-0.084-0.23380.10050.07030.0196-0.04530.08670.04140.2279122.6034176.062396.6582
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A247 - 471
2X-RAY DIFFRACTION2B745 - 755

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