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- PDB-6sjm: Crystal structure of the Retinoic Acid Receptor alpha in complex ... -

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Basic information

Entry
Database: PDB / ID: 6sjm
TitleCrystal structure of the Retinoic Acid Receptor alpha in complex with compound 24 (JP175)
Components
  • Nuclear receptor coactivator 2
  • Retinoic acid receptor RXR-alpha
KeywordsDNA BINDING PROTEIN / RXRA / steroid hormone receptor / 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 shuttle / retinoic acid binding / TGFBR3 expression ...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 shuttle / retinoic acid binding / TGFBR3 expression / 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 / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / positive regulation of bone mineralization / retinoic acid receptor signaling pathway / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / 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 / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / 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 / circadian regulation of gene expression / peptide binding / SUMOylation of intracellular receptors / Heme signaling / 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 / Nuclear Receptor transcription pathway / Activation of anterior HOX genes in hindbrain development during early embryogenesis / 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 / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / chromatin binding / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
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/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 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 / 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-LFZ / Retinoic acid receptor RXR-alpha / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 Å
AuthorsChaikuad, A. / Pollinger, J. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Merk, D. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: A Novel Biphenyl-based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences.
Authors: Pollinger, J. / Schierle, S. / Gellrich, L. / Ohrndorf, J. / Kaiser, A. / Heitel, P. / Chaikuad, A. / Knapp, S. / Merk, D.
History
DepositionAug 13, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 18, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 10, 2022Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_assembly ...database_2 / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details
Revision 1.3Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)27,9093
Polymers27,5612
Non-polymers3481
Water724
1
A: Retinoic acid receptor RXR-alpha
B: Nuclear receptor coactivator 2
hetero molecules

A: Retinoic acid receptor RXR-alpha
B: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,8196
Polymers55,1224
Non-polymers6962
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_555-y,-x,-z+1/21
Unit cell
Length a, b, c (Å)63.998, 63.998, 109.596
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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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: 25817.988 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-LFZ / 2-[4-[3,5-bis(trifluoromethyl)phenyl]phenyl]ethanoic acid


Mass: 348.240 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H10F6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 2.04 Å3/Da / Density % sol: 39.62 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 21% PEG 4000, 0.2 M ammonium acetate and 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: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.52→45.25 Å / Num. obs: 8101 / % possible obs: 99.2 % / Redundancy: 7.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.029 / Rrim(I) all: 0.08 / Net I/σ(I): 12.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.52-2.667.70.99211640.7770.3711.054100
7.97-45.256.60.0483020.9960.020.05298.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LYQ

5lyq


Resolution: 2.52→45.25 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.944 / SU B: 27.351 / SU ML: 0.275 / SU R Cruickshank DPI: 1.0686 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.069 / ESU R Free: 0.309
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.247 414 5.1 %RANDOM
Rwork0.2053 ---
obs0.2074 7675 98.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 148.94 Å2 / Biso mean: 80.634 Å2 / Biso min: 49.87 Å2
Baniso -1Baniso -2Baniso -3
1-1.35 Å2-0 Å2-0 Å2
2--1.35 Å2-0 Å2
3----2.7 Å2
Refinement stepCycle: final / Resolution: 2.52→45.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1780 0 24 4 1808
Biso mean--84.22 63.11 -
Num. residues----225
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0131839
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171777
X-RAY DIFFRACTIONr_angle_refined_deg1.1681.632488
X-RAY DIFFRACTIONr_angle_other_deg1.1561.5824111
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9955222
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.41721.64891
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.54515333
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1211513
X-RAY DIFFRACTIONr_chiral_restr0.0570.2237
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022076
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02375
LS refinement shellResolution: 2.52→2.585 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 32 -
Rwork0.249 562 -
all-594 -
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)
12.5212-0.05020.09551.68410.67354.7606-0.22480.02340.29470.05950.0233-0.2395-0.90280.04130.20150.36540.0165-0.08320.00470.01070.37289.9648.10529.0105
28.4628-0.9824-3.29877.44051.65874.108-0.14940.0504-0.38470.48630.0128-0.0930.01260.00940.13660.38060.0263-0.07440.4254-0.01570.38220.79878.019945.8969
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A228 - 457
2X-RAY DIFFRACTION2B471 - 483

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