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- PDB-3fc6: hRXRalpha & mLXRalpha with an indole Pharmacophore, SB786875 -

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Basic information

Entry
Database: PDB / ID: 3fc6
TitlehRXRalpha & mLXRalpha with an indole Pharmacophore, SB786875
Components
  • Nr1h3 protein
  • Retinoic acid receptor RXR-alpha
KeywordsTRANSCRIPTION / Liver X receptor / nuclear hormone receptors / agonists / epoxycholesterol / DNA-binding / Host-virus interaction / Metal-binding / Nucleus / Polymorphism / Receptor / Transcription regulation / Ubl conjugation / Zinc / Zinc-finger
Function / homology
Function and homology information


regulation of secretion of lysosomal enzymes / regulation of pancreatic juice secretion / negative regulation of secretion of lysosomal enzymes / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / sterol response element binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / SUMOylation of intracellular receptors / negative regulation of pancreatic juice secretion / Nuclear Receptor transcription pathway / phosphatidylcholine acyl-chain remodeling ...regulation of secretion of lysosomal enzymes / regulation of pancreatic juice secretion / negative regulation of secretion of lysosomal enzymes / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / sterol response element binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / SUMOylation of intracellular receptors / negative regulation of pancreatic juice secretion / Nuclear Receptor transcription pathway / phosphatidylcholine acyl-chain remodeling / negative regulation of macrophage activation / negative regulation of response to endoplasmic reticulum stress / negative regulation of pinocytosis / sterol homeostasis / regulation of lipid storage / positive regulation of triglyceride biosynthetic process / VLDLR internalisation and degradation / retinoic acid-responsive element binding / positive regulation of toll-like receptor 4 signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / positive regulation of thyroid hormone receptor signaling pathway / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / regulation of fatty acid metabolic process / bile acid metabolic process / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / positive regulation of fatty acid biosynthetic process / Carnitine shuttle / negative regulation of lipid transport / retinoic acid binding / positive regulation of vitamin D receptor signaling pathway / TGFBR3 expression / nuclear vitamin D receptor binding / apoptotic cell clearance / Signaling by Retinoic Acid / negative regulation of cold-induced thermogenesis / positive regulation of cholesterol transport / triglyceride homeostasis / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / DNA binding domain binding / positive regulation of lipid metabolic process / positive regulation of bone mineralization / LBD domain binding / negative regulation of cholesterol storage / nuclear steroid receptor activity / positive regulation of lipoprotein transport / lipid homeostasis / Synthesis of bile acids and bile salts / monocyte differentiation / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / positive regulation of cholesterol efflux / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / cellular response to low-density lipoprotein particle stimulus / response to retinoic acid / positive regulation of lipid biosynthetic process / nuclear retinoid X receptor binding / retinoic acid receptor signaling pathway / cell maturation / Recycling of bile acids and salts / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / intracellular receptor signaling pathway / peroxisome proliferator activated receptor signaling pathway / hormone-mediated signaling pathway / Regulation of lipid metabolism by PPARalpha / response to progesterone / negative regulation of proteolysis / peptide binding / cholesterol homeostasis / BMAL1:CLOCK,NPAS2 activates circadian expression / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Activation of gene expression by SREBF (SREBP) / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / transcription coregulator binding / lipid metabolic process / SUMOylation of intracellular receptors / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Heme signaling / PPARA activates gene expression / Cytoprotection by HMOX1 / Transcriptional activation of mitochondrial biogenesis / Nuclear Receptor transcription pathway / negative regulation of inflammatory response / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / mRNA transcription by RNA polymerase II / RNA polymerase II transcription regulator complex / nuclear receptor activity / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Transcriptional regulation of granulopoiesis / fatty acid biosynthetic process / sequence-specific double-stranded DNA binding / nervous system development / cellular response to lipopolysaccharide / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / transcription regulator complex / double-stranded DNA binding / DNA-binding transcription activator activity, RNA polymerase II-specific / sequence-specific DNA binding
Similarity search - Function
Liver X receptor / Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / : / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. ...Liver X receptor / Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / : / : / Retinoid X Receptor / Retinoid X Receptor / 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-LX2 / RETINOIC ACID / Retinoic acid receptor RXR-alpha / Nr1h3 protein / Oxysterols receptor LXR-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.063 Å
AuthorsWashburn, D.G. / Hoang, T.H. / Campobasso, N. / Smallwood, A. / Parks, D.J. / Webb, C.L. / Frank, K. / Nord, M. / Duraiswami, C. / Evans, C. ...Washburn, D.G. / Hoang, T.H. / Campobasso, N. / Smallwood, A. / Parks, D.J. / Webb, C.L. / Frank, K. / Nord, M. / Duraiswami, C. / Evans, C. / Jaye, M. / Thompson, S.K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Synthesis and SAR of potent LXR agonists containing an indole pharmacophore.
Authors: Washburn, D.G. / Hoang, T.H. / Campobasso, N. / Smallwood, A. / Parks, D.J. / Webb, C.L. / Frank, K.A. / Nord, M. / Duraiswami, C. / Evans, C. / Jaye, M. / Thompson, S.K.
History
DepositionNov 21, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 10, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 27, 2023Group: 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: Retinoic acid receptor RXR-alpha
B: Nr1h3 protein
C: Retinoic acid receptor RXR-alpha
D: Nr1h3 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,3088
Polymers115,4654
Non-polymers1,8434
Water4,125229
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11230 Å2
ΔGint-59 kcal/mol
Surface area37420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.162, 90.029, 101.642
Angle α, β, γ (deg.)90.00, 111.92, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Retinoic acid receptor RXR-alpha / Retinoid X receptor alpha / Nuclear receptor subfamily 2 group B member 1


Mass: 27114.465 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P19793
#2: Protein Nr1h3 protein / Putative uncharacterized protein / Nuclear receptor subfamily 1 group H member 3 / Nuclear receptor ...Putative uncharacterized protein / Nuclear receptor subfamily 1 group H member 3 / Nuclear receptor subfamily 1 / group H / member 3 / Nuclear receptor subfamily 1 / group H / member 3 / isoform CRA_a


Mass: 30618.035 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q91X41, UniProt: Q9Z0Y9*PLUS
#3: Chemical ChemComp-REA / RETINOIC ACID


Mass: 300.435 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H28O2
#4: Chemical ChemComp-LX2 / [4-(3-{[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino}propoxy)-1H-indol-1-yl]acetic acid


Mass: 621.088 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H32ClF3N2O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 229 / 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: 2.25 Å3/Da / Density % sol: 45.22 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 23, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.06→44.2 Å / Num. all: 62907 / Num. obs: 58748 / % possible obs: 93.4 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.7 % / Biso Wilson estimate: 26.1 Å2 / Rmerge(I) obs: 0.082 / Rsym value: 0.082 / Net I/σ(I): 7.9
Reflection shellResolution: 2.06→2.13 Å / Rmerge(I) obs: 0.376 / Mean I/σ(I) obs: 2.2 / % possible all: 71.3

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Processing

Software
NameVersionClassification
HKL-2000data collection
MLPHAREphasing
PHENIX(phenix.refine)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.063→44.2 Å / SU ML: 0.34 / σ(F): 0.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2501 2820 5.07 %
Rwork0.1987 --
obs0.2014 55572 88.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 31.174 Å2 / ksol: 0.342 e/Å3
Refinement stepCycle: LAST / Resolution: 2.063→44.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7150 0 132 229 7511
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.063-2.09810.3673810.26751647X-RAY DIFFRACTION55
2.0981-2.13630.33581140.2661953X-RAY DIFFRACTION66
2.1363-2.17730.32851260.24962150X-RAY DIFFRACTION72
2.1773-2.22180.29961100.23442273X-RAY DIFFRACTION76
2.2218-2.27010.30371260.21672356X-RAY DIFFRACTION80
2.2701-2.32290.28091450.20662529X-RAY DIFFRACTION85
2.3229-2.3810.26931470.20022631X-RAY DIFFRACTION89
2.381-2.44540.2391430.19942685X-RAY DIFFRACTION90
2.4454-2.51730.23351400.20952736X-RAY DIFFRACTION92
2.5173-2.59850.28671410.21682750X-RAY DIFFRACTION92
2.5985-2.69140.27111490.21692770X-RAY DIFFRACTION93
2.6914-2.79920.25751590.22232807X-RAY DIFFRACTION94
2.7992-2.92650.29331360.20762863X-RAY DIFFRACTION95
2.9265-3.08080.26931500.21642889X-RAY DIFFRACTION96
3.0808-3.27370.24011670.21242879X-RAY DIFFRACTION97
3.2737-3.52640.24581340.19792942X-RAY DIFFRACTION98
3.5264-3.88110.2041830.17412928X-RAY DIFFRACTION98
3.8811-4.44230.21181610.15112960X-RAY DIFFRACTION99
4.4423-5.5950.2071570.16642982X-RAY DIFFRACTION99
5.595-44.23130.21641510.1763022X-RAY DIFFRACTION98

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