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- PDB-4dqm: Revealing a marine natural product as a novel agonist for retinoi... -

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Basic information

Entry
Database: PDB / ID: 4dqm
TitleRevealing a marine natural product as a novel agonist for retinoic acid receptors with a unique binding mode and antitumor activity
Components
  • Nuclear receptor coactivator 1
  • Retinoic acid receptor alpha
KeywordsTRANSCRIPTION/TRANSFERASE / nuclear receptor transcription factor / ligand binding domain / Transcription regulation / Nucleus / TRANSCRIPTION-TRANSFERASE complex
Function / homology
Function and homology information


Sertoli cell fate commitment / positive regulation of binding / trachea cartilage development / ventricular cardiac muscle cell differentiation / embryonic camera-type eye development / chondroblast differentiation / protein kinase B binding / glandular epithelial cell development / negative regulation of granulocyte differentiation / growth plate cartilage development ...Sertoli cell fate commitment / positive regulation of binding / trachea cartilage development / ventricular cardiac muscle cell differentiation / embryonic camera-type eye development / chondroblast differentiation / protein kinase B binding / glandular epithelial cell development / negative regulation of granulocyte differentiation / growth plate cartilage development / positive regulation of T-helper 2 cell differentiation / prostate gland development / negative regulation of cartilage development / retinoic acid-responsive element binding / regulation of hematopoietic progenitor cell differentiation / positive regulation of interleukin-13 production / positive regulation of interleukin-5 production / retinoic acid binding / labyrinthine layer morphogenesis / response to vitamin A / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / apoptotic cell clearance / positive regulation of female receptivity / ureteric bud development / limb development / heterocyclic compound binding / Signaling by Retinoic Acid / regulation of myelination / protein kinase A binding / DNA-binding transcription repressor activity / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of interleukin-4 production / face development / alpha-actinin binding / germ cell development / negative regulation of type II interferon production / cellular response to Thyroglobulin triiodothyronine / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts / estrous cycle / cellular response to estrogen stimulus / positive regulation of cell cycle / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / retinoic acid receptor signaling pathway / progesterone receptor signaling pathway / nuclear retinoid X receptor binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / response to retinoic acid / histone acetyltransferase activity / cellular response to retinoic acid / Recycling of bile acids and salts / histone acetyltransferase / cellular response to hormone stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / regulation of cellular response to insulin stimulus / mRNA regulatory element binding translation repressor activity / cerebellum development / liver development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / negative regulation of miRNA transcription / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to cytokine / nuclear receptor coactivator activity / neural tube closure / hippocampus development / response to progesterone / nuclear receptor binding / female pregnancy / nuclear estrogen receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / regulation of synaptic plasticity / PPARA activates gene expression / Cytoprotection by HMOX1 / multicellular organism growth / chromatin DNA binding / cerebral cortex development / mRNA 5'-UTR binding / transcription coactivator binding / histone deacetylase binding / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / Activation of anterior HOX genes in hindbrain development during early embryogenesis
Similarity search - Function
: / : / Retinoic acid 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 ...: / : / Retinoic acid 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 / 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-LUF / Retinoic acid receptor alpha / Nuclear receptor coactivator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.75 Å
AuthorsWang, S. / Wang, Z. / Lin, S. / Zheng, W. / Wang, R. / Jin, S. / Chen, J. / Jin, L. / Li, Y.
CitationJournal: Biochem.J. / Year: 2012
Title: Revealing a natural marine product as a novel agonist for retinoic acid receptors with a unique binding mode and inhibitory effects on cancer cells.
Authors: Wang, S. / Wang, Z. / Lin, S. / Zheng, W. / Wang, R. / Jin, S. / Chen, J. / Jin, L. / Li, Y.
History
DepositionFeb 16, 2012Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 16, 2014Group: Experimental preparation
Revision 1.2Nov 15, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software / Item: _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Retinoic acid receptor alpha
B: Nuclear receptor coactivator 1
C: Retinoic acid receptor alpha
D: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,0926
Polymers55,3194
Non-polymers7732
Water55831
1
A: Retinoic acid receptor alpha
B: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0463
Polymers27,6592
Non-polymers3871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area950 Å2
ΔGint-9 kcal/mol
Surface area11290 Å2
MethodPISA
2
C: Retinoic acid receptor alpha
D: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0463
Polymers27,6592
Non-polymers3871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint-9 kcal/mol
Surface area11220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.120, 104.460, 113.480
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein Retinoic acid receptor alpha / RAR-alpha / Nuclear receptor subfamily 1 group B member 1


Mass: 26485.908 Da / Num. of mol.: 2 / Fragment: ligand binding domain, UNP RESIDUES 182-415
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR1B1, RARA / Plasmid: pET24a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P10276
#2: Protein/peptide Nuclear receptor coactivator 1 / NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal ...NCoA-1 / Class E basic helix-loop-helix protein 74 / bHLHe74 / Protein Hin-2 / RIP160 / Renal carcinoma antigen NY-REN-52 / Steroid receptor coactivator 1 / SRC-1


Mass: 1173.379 Da / Num. of mol.: 2 / Fragment: LXXLL motif 7, UNP RESIDUES 1432-1441 / Source method: obtained synthetically / Details: The peptide was chemically synthesized. / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15788, histone acetyltransferase
#3: Chemical ChemComp-LUF / (5S)-4-[(3E,7E)-4,8-dimethyl-10-(2,6,6-trimethylcyclohex-1-en-1-yl)deca-3,7-dien-1-yl]-5-hydroxyfuran-2(5H)-one / Luffariellolide


Mass: 386.567 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H38O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / 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: 2.9 Å3/Da / Density % sol: 57.58 % / Mosaicity: 0.748 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 2% v/v Tacsimate pH7.0, 5% 2-propanol, 0.1M imadazole , 8% PEG 3350, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 1.5619 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 29, 2010
RadiationMonochromator: Diamond [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5619 Å / Relative weight: 1
ReflectionResolution: 2.55→50 Å / Num. obs: 17478 / % possible obs: 98.5 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 7.4 % / Rmerge(I) obs: 0.092 / Χ2: 1.295 / Net I/σ(I): 8.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.75-2.87.70.6488400.673199.8
2.8-2.857.70.4998640.686199.7
2.85-2.97.40.3998190.715199.4
2.9-2.966.90.2948270.749198.6
2.96-3.037.30.2798380.752199.6
3.03-3.17.70.2538360.751199.9
3.1-3.1780.2528540.785199.9
3.17-3.2680.2188540.861199.9
3.26-3.368.10.1888530.9611100
3.36-3.464.70.1467762.917191.7
3.46-3.597.40.1748631.606199.8
3.59-3.7360.1638242.513199
3.73-3.95.70.1168302.758195.1
3.9-4.117.30.0737541.147188.7
4.11-4.368.10.0628661.1891100
4.36-4.780.0638721.551100
4.7-5.177.90.0658721.981100
5.17-5.927.90.0698852.0081100
5.92-7.467.80.0529011.4121100
7.46-5070.0289671.267199.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.75→47.46 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.931 / WRfactor Rfree: 0.2542 / WRfactor Rwork: 0.2085 / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.787 / SU B: 12.51 / SU ML: 0.263 / SU R Cruickshank DPI: 0.8852 / SU Rfree: 0.3374 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.885 / ESU R Free: 0.337 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2594 922 5 %RANDOM
Rwork0.2134 ---
all0.2157 20596 --
obs0.2157 16995 84.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 152.97 Å2 / Biso mean: 62.5045 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å20 Å20 Å2
2--0.15 Å20 Å2
3----0.05 Å2
Refinement stepCycle: LAST / Resolution: 2.75→47.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3855 0 54 31 3940
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.023968
X-RAY DIFFRACTIONr_angle_refined_deg1.752.0185360
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1455484
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.10924.815162
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.76815763
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.1471526
X-RAY DIFFRACTIONr_chiral_restr0.1020.2636
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212863
LS refinement shellResolution: 2.549→2.615 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 62 -
Rwork0.321 1139 -
all-1201 -
obs--82.04 %

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