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- PDB-3omo: Fragment-Based Design of novel Estrogen Receptor Ligands -

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Basic information

Entry
Database: PDB / ID: 3omo
TitleFragment-Based Design of novel Estrogen Receptor Ligands
Components
  • Estrogen receptor beta
  • Nuclear receptor coactivator 1
KeywordsPROTEIN BINDING / Steroid binding
Function / homology
Function and homology information


receptor antagonist activity / labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / nuclear steroid receptor activity / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / nuclear estrogen receptor activity ...receptor antagonist activity / labyrinthine layer morphogenesis / regulation of thyroid hormone receptor signaling pathway / positive regulation of transcription from RNA polymerase II promoter by galactose / positive regulation of female receptivity / nuclear steroid receptor activity / hypothalamus development / male mating behavior / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / nuclear estrogen receptor activity / cellular response to Thyroglobulin triiodothyronine / Synthesis of bile acids and bile salts / estrous cycle / cellular response to estrogen stimulus / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / estrogen response element binding / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / 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 / 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 / steroid binding / lactation / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / regulation of cellular response to insulin stimulus / ESR-mediated signaling / cerebellum development / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / cellular response to estradiol stimulus / response to progesterone / nuclear receptor binding / nuclear estrogen receptor binding / hippocampus development / RNA polymerase II transcription regulatory region sequence-specific DNA binding / positive regulation of DNA-binding transcription factor activity / Heme signaling / mRNA transcription by RNA polymerase II / Transcriptional activation of mitochondrial biogenesis / negative regulation of cell growth / PPARA activates gene expression / Cytoprotection by HMOX1 / cerebral cortex development / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / male gonad development / Circadian Clock / PIP3 activates AKT signaling / cell-cell signaling / response to estradiol / HATs acetylate histones / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Estrogen-dependent gene expression / transcription regulator complex / Extra-nuclear estrogen signaling / transcription coactivator activity / protein dimerization activity / DNA-binding transcription factor activity, RNA polymerase II-specific / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / intracellular membrane-bounded organelle / chromatin binding / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / DNA binding / zinc ion binding / nucleoplasm / nucleus / plasma membrane / cytosol
Similarity search - Function
Estrogen receptor beta-like, N-terminal / Estrogen receptor beta/gamma / Estrogen receptor beta / Nuclear receptor coactivator 1 / Estrogen receptor/oestrogen-related receptor / 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 ...Estrogen receptor beta-like, N-terminal / Estrogen receptor beta/gamma / Estrogen receptor beta / Nuclear receptor coactivator 1 / Estrogen receptor/oestrogen-related receptor / 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-WV7 / Nuclear receptor coactivator 1 / Estrogen receptor beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.21 Å
AuthorsMoecklinghoff, S. / van Otterlo, W.A. / Rose, R. / Fuchs, S. / Dominguez Seoane, M. / Waldmann, H. / Ottmann, C. / Brunsveld, L.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Design and Evaluation of Fragment-Like Estrogen Receptor Tetrahydroisoquinoline Ligands from a Scaffold-Detection Approach.
Authors: van Otterlo, W.A. / Rose, R. / Fuchs, S. / Zimmermann, T.J. / Dominguez Seoane, M. / Waldmann, H. / Ottmann, C. / Brunsveld, L.
History
DepositionAug 27, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2011Provider: 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Estrogen receptor beta
B: Estrogen receptor beta
C: Nuclear receptor coactivator 1
D: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,1786
Polymers58,6874
Non-polymers4902
Water5,999333
1
A: Estrogen receptor beta
C: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,5893
Polymers29,3442
Non-polymers2451
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1090 Å2
ΔGint-8 kcal/mol
Surface area11540 Å2
MethodPISA
2
B: Estrogen receptor beta
D: Nuclear receptor coactivator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,5893
Polymers29,3442
Non-polymers2451
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1010 Å2
ΔGint-8 kcal/mol
Surface area11600 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4940 Å2
ΔGint-33 kcal/mol
Surface area20300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.570, 70.570, 109.990
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A1 - 1000
2114B1 - 1000

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Components

#1: Protein Estrogen receptor beta / ER-beta / Nuclear receptor subfamily 3 group A member 2


Mass: 27109.143 Da / Num. of mol.: 2 / Fragment: Ligand Binding Domain (UNP residues 261-500)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR2, ESTRB, NR3A2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q92731
#2: Protein/peptide Nuclear receptor coactivator 1 / NCoA-1 / Steroid receptor coactivator 1 / SRC-1 / RIP160 / Protein Hin-2 / Renal carcinoma antigen ...NCoA-1 / Steroid receptor coactivator 1 / SRC-1 / RIP160 / Protein Hin-2 / Renal carcinoma antigen NY-REN-52 / Class E basic helix-loop-helix protein 74 / bHLHe74


Mass: 2234.535 Da / Num. of mol.: 2 / Fragment: Box 2 (UNP residues 683-701) / Source method: obtained synthetically / Details: Synthetic Peptide / References: UniProt: Q15788
#3: Chemical ChemComp-WV7 / 2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-ol


Mass: 245.198 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H10F3NO2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 333 / 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: 2.69 Å3/Da / Density % sol: 54.35 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.2 M Ammonium Acetate, 0.1 M BIS-TRIS pH 5.5, 17% PEG10000 (v/v), VAPOR DIFFUSION, HANGING DROP, temperature 277.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: MARRESEARCH / Detector: AREA DETECTOR / Date: Jun 24, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→20 Å / Num. obs: 29488 / % possible obs: 94.9 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 26.74 Å2 / Rmerge(I) obs: 0.048 / Net I/σ(I): 11.76
Reflection shell
Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique obs% possible all
2.2-2.50.1335.414482889590.2
2.5-30.0798.514652882498.7
3-3.50.04514.27552448498.5
3.5-40.03219.84211246297.4
4-50.027234251243296.1
5-100.02921.73959214792.1
10-150.02233.238819785.7
15-200.02132.2954785.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASERphasing
REFMAC5.5.0109refinement
PDB_EXTRACT3.1data extraction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.21→19.54 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.874 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 5.829 / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2638 1475 5 %RANDOM
Rwork0.2084 ---
obs0.2111 29488 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 65.73 Å2 / Biso mean: 20.5507 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20.03 Å20 Å2
2--0.05 Å20 Å2
3----0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.21→19.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3747 0 34 333 4114
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0223869
X-RAY DIFFRACTIONr_angle_refined_deg2.00525234
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4565471
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.29123.889144
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.17715746
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4751521
X-RAY DIFFRACTIONr_chiral_restr0.1280.2622
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212739
X-RAY DIFFRACTIONr_mcbond_it1.1111.52377
X-RAY DIFFRACTIONr_mcangle_it2.05123843
X-RAY DIFFRACTIONr_scbond_it3.65531492
X-RAY DIFFRACTIONr_scangle_it5.5544.51391
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 1745 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
MEDIUM POSITIONAL0.320.5
MEDIUM THERMAL0.832
LS refinement shellResolution: 2.212→2.269 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.388 93 -
Rwork0.267 1759 -
all-1852 -
obs--100 %

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