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- PDB-8pp0: Crystal structure of Retinoic Acid Receptor alpha (RXRA) in compl... -

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Basic information

Entry
Database: PDB / ID: 8pp0
TitleCrystal structure of Retinoic Acid Receptor alpha (RXRA) in complexed with JP147
Components
  • Nuclear receptor coactivator 2
  • Retinoic acid receptor RXR-alpha
KeywordsDNA BINDING PROTEIN / RXR alpha / inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


positive regulation of transporter activity / retinoic acid-responsive element binding / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / positive regulation of thyroid hormone receptor signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / Carnitine metabolism / ion binding / Regulation of pyruvate dehydrogenase (PDH) complex ...positive regulation of transporter activity / retinoic acid-responsive element binding / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / positive regulation of thyroid hormone receptor signaling pathway / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / Carnitine metabolism / ion binding / Regulation of pyruvate dehydrogenase (PDH) complex / retinoic acid binding / positive regulation of vitamin D receptor signaling pathway / nuclear vitamin D receptor binding / Signaling by Retinoic Acid / DNA binding domain binding / nuclear steroid receptor activity / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / LBD domain binding / locomotor rhythm / aryl hydrocarbon receptor binding / regulation of lipid metabolic process / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / positive regulation of cholesterol efflux / retinoic acid receptor signaling pathway / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / positive regulation of bone mineralization / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / response to retinoic acid / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / 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 / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / 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 / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / circadian regulation of gene expression / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / Transcriptional regulation of white adipocyte differentiation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Nuclear Receptor transcription pathway / Transcriptional regulation of granulopoiesis / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / Circadian Clock / HATs acetylate histones / double-stranded DNA binding / Estrogen-dependent gene expression / transcription regulator complex / sequence-specific DNA binding / transcription coactivator activity / cell differentiation / receptor complex / nuclear body / protein dimerization activity / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / chromatin binding / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 ...Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 / 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
Similarity search - Domain/homology
: / Retinoic acid receptor RXR-alpha / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsChaikuad, A. / Pollinger, J. / Merk, D. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Guided Design of a Highly Potent Partial RXR Agonist with Superior Physicochemical Properties.
Authors: Lewandowski, M. / Carmina, M. / Knumann, L. / Sai, M. / Willems, S. / Kasch, T. / Pollinger, J. / Knapp, S. / Marschner, J.A. / Chaikuad, A. / Merk, D.
History
DepositionJul 5, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,1993
Polymers28,8172
Non-polymers3811
Water1,44180
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1110 Å2
ΔGint-9 kcal/mol
Surface area10890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.648, 65.648, 110.816
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-652-

HOH

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Components

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


Mass: 27074.312 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RXRA, NR2B1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2 / References: UniProt: P19793
#2: Protein/peptide Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1743.039 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-7QJ / 3-[4-[2,3-dihydro-1H-inden-4-yl(methyl)amino]-6-(trifluoromethyl)pyrimidin-2-yl]oxypropanoic acid


Mass: 381.349 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18F3N3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.07 Å3/Da / Density % sol: 40.62 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 23% PEG 3350, 0.1 M Ammonium actetate, 0.1 M tris pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 27, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.9→46.42 Å / Num. obs: 19823 / % possible obs: 99.9 % / Redundancy: 7.8 % / CC1/2: 1 / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.015 / Rrim(I) all: 0.042 / Χ2: 0.99 / Net I/σ(I): 20.7
Reflection shellResolution: 1.9→2 Å / Redundancy: 8.1 % / Rmerge(I) obs: 0.982 / Mean I/σ(I) obs: 2 / Num. unique obs: 2833 / CC1/2: 0.849 / Rpim(I) all: 0.397 / Rrim(I) all: 1.134 / Χ2: 0.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→42.85 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.958 / SU B: 8.801 / SU ML: 0.121 / Cross valid method: THROUGHOUT / ESU R: 0.143 / ESU R Free: 0.137 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2226 946 4.8 %RANDOM
Rwork0.17984 ---
obs0.18187 18819 99.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 53.195 Å2
Baniso -1Baniso -2Baniso -3
1-1.46 Å20 Å20 Å2
2--1.46 Å2-0 Å2
3----2.93 Å2
Refinement stepCycle: 1 / Resolution: 1.9→42.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1789 0 27 80 1896
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0131867
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171804
X-RAY DIFFRACTIONr_angle_refined_deg1.3681.6362530
X-RAY DIFFRACTIONr_angle_other_deg1.3361.5884177
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1815228
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.08221.6392
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.39115333
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3821513
X-RAY DIFFRACTIONr_chiral_restr0.0840.2241
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.022105
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02378
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9693.892910
X-RAY DIFFRACTIONr_mcbond_other2.9693.885909
X-RAY DIFFRACTIONr_mcangle_it4.3385.7881132
X-RAY DIFFRACTIONr_mcangle_other4.3375.7971133
X-RAY DIFFRACTIONr_scbond_it3.7524.297957
X-RAY DIFFRACTIONr_scbond_other3.7514.296957
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.626.3231397
X-RAY DIFFRACTIONr_long_range_B_refined7.81446.62057
X-RAY DIFFRACTIONr_long_range_B_other7.81146.4572043
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.353 64 -
Rwork0.324 1366 -
obs--99.93 %
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)
11.4990.1620.11140.3207-0.00970.9684-0.00690.18630.08770.18590.0288-0.0838-0.2136-0.0116-0.02190.18790.045-0.04660.06350.01350.035610.46937.679229.2723
26.98820.0462-1.2977.1812-0.98631.5463-0.2803-0.1773-0.49930.37860.1542-0.2862-0.0358-0.18230.12610.2518-0.0002-0.09210.04210.01690.0921.1548.661546.1597
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A228 - 458
2X-RAY DIFFRACTION2B472 - 483

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