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- PDB-6b0f: ESTROGEN RECEPTOR ALPHA LIGAND BINDING DOMAIN IN COMPLEX WITH LSZ102 -

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Basic information

Entry
Database: PDB / ID: 6b0f
TitleESTROGEN RECEPTOR ALPHA LIGAND BINDING DOMAIN IN COMPLEX WITH LSZ102
ComponentsEstrogen receptor
KeywordsHORMONE RECEPTOR / nuclear receptor
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / nuclear estrogen receptor activity / epithelial cell proliferation involved in mammary gland duct elongation ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / nuclear estrogen receptor activity / epithelial cell proliferation involved in mammary gland duct elongation / epithelial cell development / prostate epithelial cord elongation / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / TFIIB-class transcription factor binding / androgen metabolic process / steroid hormone receptor signaling pathway / mammary gland alveolus development / estrogen receptor signaling pathway / cellular response to estrogen stimulus / estrogen response element binding / : / nuclear receptor-mediated steroid hormone signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / protein localization to chromatin / 14-3-3 protein binding / TBP-class protein binding / nitric-oxide synthase regulator activity / steroid binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / ESR-mediated signaling / transcription corepressor binding / negative regulation of miRNA transcription / positive regulation of nitric-oxide synthase activity / cellular response to estradiol stimulus / transcription coregulator binding / stem cell differentiation / nuclear estrogen receptor binding / SUMOylation of intracellular receptors / euchromatin / negative regulation of DNA-binding transcription factor activity / beta-catenin binding / transcription coactivator binding / positive regulation of DNA-binding transcription factor activity / Nuclear Receptor transcription pathway / response to estrogen / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / male gonad development / positive regulation of nitric oxide biosynthetic process / sequence-specific double-stranded DNA binding / positive regulation of fibroblast proliferation / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / ATPase binding / regulation of inflammatory response / fibroblast proliferation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / Extra-nuclear estrogen signaling / calmodulin binding / DNA-binding transcription factor activity, RNA polymerase II-specific / chromatin remodeling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / chromatin binding / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of DNA-templated transcription / Golgi apparatus / enzyme binding / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding / membrane / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. ...Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / Retinoid X Receptor / Retinoid X Receptor / 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
LSZ102 / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.86 Å
AuthorsKirby, C.A. / Baird, J.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.
Authors: Tria, G.S. / Abrams, T. / Baird, J. / Burks, H.E. / Firestone, B. / Gaither, L.A. / Hamann, L.G. / He, G. / Kirby, C.A. / Kim, S. / Lombardo, F. / Macchi, K.J. / McDonnell, D.P. / Mishina, Y. ...Authors: Tria, G.S. / Abrams, T. / Baird, J. / Burks, H.E. / Firestone, B. / Gaither, L.A. / Hamann, L.G. / He, G. / Kirby, C.A. / Kim, S. / Lombardo, F. / Macchi, K.J. / McDonnell, D.P. / Mishina, Y. / Norris, J.D. / Nunez, J. / Springer, C. / Sun, Y. / Thomsen, N.M. / Wang, C. / Wang, J. / Yu, B. / Tiong-Yip, C.L. / Peukert, S.
History
DepositionSep 14, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 4, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Dec 25, 2019Group: Derived calculations / Structure summary / Category: chem_comp / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,0137
Polymers57,7962
Non-polymers1,2175
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3280 Å2
ΔGint-6 kcal/mol
Surface area17620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.820, 52.100, 97.020
Angle α, β, γ (deg.)90.00, 114.33, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 28897.877 Da / Num. of mol.: 2 / Fragment: residues 301-553 / Mutation: C381S, C417S, C530S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli (E. coli) / References: UniProt: P03372
#2: Chemical ChemComp-C6V / LSZ102 / (2E)-3-[4-({2-[2-(1,1-difluoroethyl)-4-fluorophenyl]-6-hydroxy-1-benzothiophen-3-yl}oxy)phenyl]prop-2-enoic acid


Mass: 470.460 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H17F3O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.11 Å3/Da / Density % sol: 41.66 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop
Details: 0.1 M TRIS-HCL (PH 8.5), 22% PEG 3350, 0.20 M MAGNESIUM CHLORIDE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 6, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.86→48.21 Å / Num. obs: 11212 / % possible obs: 98.8 % / Redundancy: 3.2 % / Biso Wilson estimate: 68.62 Å2 / Rmerge(I) obs: 0.117 / Net I/σ(I): 7.3
Reflection shellResolution: 2.86→2.87 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.583 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 107 / % possible all: 99.1

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Processing

Software
NameVersionClassification
XDSdata reduction
SCALAdata scaling
BUSTER2.11.7refinement
BUSTER2.11.7phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1MTYS

Resolution: 2.86→45.84 Å / Cor.coef. Fo:Fc: 0.875 / Cor.coef. Fo:Fc free: 0.81 / Cross valid method: FREE R-VALUE / σ(F): 0 / SU Rfree Blow DPI: 0.445
RfactorNum. reflection% reflectionSelection details
Rfree0.299 538 4.8 %RANDOM
Rwork0.227 ---
obs0.231 11202 98.6 %-
Displacement parametersBiso max: 142.01 Å2 / Biso mean: 51.9 Å2 / Biso min: 8.27 Å2
Baniso -1Baniso -2Baniso -3
1-20.0625 Å2-3.0401 Å2-17.0224 Å2
2--0 Å2-0.0551 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: LAST / Resolution: 2.86→45.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3098 0 84 17 3199
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1156SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes73HARMONIC2
X-RAY DIFFRACTIONt_gen_planes446HARMONIC5
X-RAY DIFFRACTIONt_it3233HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion407SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3785SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3233HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4360HARMONIC21.15
X-RAY DIFFRACTIONt_omega_torsion2.37
X-RAY DIFFRACTIONt_other_torsion20.6
LS refinement shellResolution: 2.86→3.13 Å / Rfactor Rfree error: 0 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3068 143 5.35 %
Rwork0.2166 2529 -
all0.2214 2672 -
obs--99.41 %

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