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- PDB-3fli: Discovery of XL335, a Highly Potent, Selective and Orally-Active ... -

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Basic information

Entry
Database: PDB / ID: 3fli
TitleDiscovery of XL335, a Highly Potent, Selective and Orally-Active Agonist of the Farnesoid X Receptor (FXR)
ComponentsBile acid receptor
KeywordsTRANSCRIPTION / FXR / BAR / NR1H4 / BILE ACID RECEPTOR / NUCLEAR RECEPTOR / LIGAND-BINDING DOMAIN / ALPHA-HELICAL SANDWICH / TRANSCRIPTIONAL REGULATOR / DNA-BINDING / METAL-BINDING / NUCLEUS / REPRESSOR / Activator / Alternative splicing / Receptor / Transcription regulation / Zinc / Zinc-finger
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 / bile acid binding / cell-cell junction assembly / bile acid signaling pathway / cellular response to fatty acid / negative regulation of interleukin-2 production / regulation of cholesterol metabolic process / 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 / negative regulation of tumor necrosis factor-mediated signaling pathway / 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 / negative regulation of canonical NF-kappaB signal transduction / Recycling of bile acids and salts / Notch signaling pathway / positive regulation of adipose tissue development / transcription coregulator binding / cholesterol homeostasis / 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 / 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 / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / 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
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. / c4 zinc finger in nuclear hormone receptors ...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-33Y / Bile acid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsFoster, P.G. / Stout, T.J.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR).
Authors: Flatt, B. / Martin, R. / Wang, T.L. / Mahaney, P. / Murphy, B. / Gu, X.H. / Foster, P. / Li, J. / Pircher, P. / Petrowski, M. / Schulman, I. / Westin, S. / Wrobel, J. / Yan, G. / Bischoff, E. ...Authors: Flatt, B. / Martin, R. / Wang, T.L. / Mahaney, P. / Murphy, B. / Gu, X.H. / Foster, P. / Li, J. / Pircher, P. / Petrowski, M. / Schulman, I. / Westin, S. / Wrobel, J. / Yan, G. / Bischoff, E. / Daige, C. / Mohan, R.
History
DepositionDec 18, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
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: Bile acid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,3852
Polymers26,9471
Non-polymers4381
Water4,017223
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.519, 66.519, 125.434
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 / Farnesoid X-activated receptor / Farnesol receptor HRR-1 / Nuclear receptor subfamily 1 group H ...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: 26946.918 Da / Num. of mol.: 1 / Fragment: Ligand Binding Domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BAR, FXR, HRR1, NR1H4, RIP14 / Plasmid: PET15b / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta (DE3) / References: UniProt: Q96RI1
#2: Chemical ChemComp-33Y / 1-methylethyl 3-[(3,4-difluorophenyl)carbonyl]-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate


Mass: 438.466 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24F2N2O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 223 / 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: 2.57 Å3/Da / Density % sol: 52.22 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 22% PEG4K, 150 mM sodium acetate, 75 mM Tris, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 18, 2004
RadiationMonochromator: Single crystal, cylindrically bent, Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→66.519 Å / Num. obs: 19746 / % possible obs: 96.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2→2.11 Å / % possible all: 93.8

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
MOLREPphasing
REFMAC5.2.0005refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→58.72 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.925 / SU B: 7.295 / SU ML: 0.113 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.179 / ESU R Free: 0.169 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24254 978 5.1 %RANDOM
Rwork0.19011 ---
obs0.19279 18017 96.2 %-
all-19746 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.425 Å2
Baniso -1Baniso -2Baniso -3
1-0.39 Å20 Å20 Å2
2--0.39 Å20 Å2
3----0.78 Å2
Refinement stepCycle: LAST / Resolution: 2→58.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1797 0 32 223 2052
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0221868
X-RAY DIFFRACTIONr_bond_other_d0.0010.021705
X-RAY DIFFRACTIONr_angle_refined_deg1.6631.9892528
X-RAY DIFFRACTIONr_angle_other_deg0.95133985
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7685219
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.08425.11488
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.60715347
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.121158
X-RAY DIFFRACTIONr_chiral_restr0.1130.2284
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.022016
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02353
X-RAY DIFFRACTIONr_nbd_refined0.230.2457
X-RAY DIFFRACTIONr_nbd_other0.1770.21716
X-RAY DIFFRACTIONr_nbtor_refined0.1790.2910
X-RAY DIFFRACTIONr_nbtor_other0.0890.2994
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1930.2168
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1640.215
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1990.227
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2920.27
X-RAY DIFFRACTIONr_mcbond_it1.1911.51462
X-RAY DIFFRACTIONr_mcbond_other0.2481.5440
X-RAY DIFFRACTIONr_mcangle_it1.38421797
X-RAY DIFFRACTIONr_scbond_it2.3123886
X-RAY DIFFRACTIONr_scangle_it3.3084.5731
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 66 -
Rwork0.225 1224 -
obs--91.17 %

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