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- PDB-5t97: ESTROGEN RECEPTOR ALPHA LIGAND BINDING DOMAIN IN COMPLEX WITH (2E... -

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Basic information

Entry
Database: PDB / ID: 5t97
TitleESTROGEN RECEPTOR ALPHA LIGAND BINDING DOMAIN IN COMPLEX WITH (2E)-3-(4-{(1R)-6-hydroxy-1-methyl-2-[4-(propan-2 -yl)phenyl]-1,2,3,4- tetrahydroisoquinolin-1-yl}phenyl)prop-2-enoic acid
ComponentsEstrogen receptor
KeywordsHORMONE RECEPTOR / NUCLEAR RECEPTOR / PROTEIN-LIGAND COMPLEX
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / 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 / nuclear estrogen receptor activity / epithelial cell development / steroid hormone receptor signaling pathway / epithelial cell proliferation involved in mammary gland duct elongation ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / 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 / nuclear estrogen receptor activity / epithelial cell development / steroid hormone receptor signaling pathway / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / mammary gland branching involved in pregnancy / uterus development / negative regulation of smooth muscle cell apoptotic process / vagina development / TFIIB-class transcription factor binding / androgen metabolic process / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / Mitochondrial unfolded protein response (UPRmt) / nuclear receptor-mediated steroid hormone signaling pathway / positive regulation of DNA-binding transcription factor activity / negative regulation of DNA-binding transcription factor activity / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / positive regulation of nitric-oxide synthase activity / estrogen receptor signaling pathway / protein localization to chromatin / steroid binding / 14-3-3 protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / negative regulation of canonical NF-kappaB signal transduction / ESR-mediated signaling / negative regulation of miRNA transcription / TBP-class protein binding / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / transcription corepressor binding / transcription coregulator binding / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / transcription coactivator binding / male gonad development / nuclear receptor activity / positive regulation of fibroblast proliferation / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of RUNX2 expression and activity / positive regulation of nitric oxide biosynthetic process / sequence-specific double-stranded DNA binding / Ovarian tumor domain proteases / response to estradiol / PIP3 activates AKT signaling / positive regulation of cytosolic calcium ion concentration / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of inflammatory response / DNA-binding transcription activator activity, RNA polymerase II-specific / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / transcription regulator complex / Estrogen-dependent gene expression / DNA-binding transcription factor activity, RNA polymerase II-specific / calmodulin binding / Extra-nuclear estrogen signaling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin remodeling / DNA-binding transcription factor activity / negative regulation of gene expression / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / protein kinase binding / chromatin / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / Golgi apparatus / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding / nucleus / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / Estrogen receptor/oestrogen-related receptor / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor ...Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / 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 / Double treble clef zinc finger, C4 type / 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-782 / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3 Å
AuthorsKirby, C.A. / Baird, J.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ER alpha + Breast Cancer.
Authors: Burks, H.E. / Abrams, T. / Kirby, C.A. / Baird, J. / Fekete, A. / Hamann, L.G. / Kim, S. / Lombardo, F. / Loo, A. / Lubicka, D. / Macchi, K. / McDonnell, D.P. / Mishina, Y. / Norris, J.D. / ...Authors: Burks, H.E. / Abrams, T. / Kirby, C.A. / Baird, J. / Fekete, A. / Hamann, L.G. / Kim, S. / Lombardo, F. / Loo, A. / Lubicka, D. / Macchi, K. / McDonnell, D.P. / Mishina, Y. / Norris, J.D. / Nunez, J. / Saran, C. / Sun, Y. / Thomsen, N.M. / Wang, C. / Wang, J. / Peukert, S.
History
DepositionSep 9, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2017Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_radiation_wavelength.wavelength

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)58,6514
Polymers57,7962
Non-polymers8552
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2610 Å2
ΔGint-6 kcal/mol
Surface area16920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.920, 51.800, 95.170
Angle α, β, γ (deg.)90.000, 113.130, 90.000
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
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-782 / (2E)-3-(4-{(1R)-6-hydroxy-1-methyl-2-[4-(propan-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-1-yl}phenyl)prop-2-enoic acid


Mass: 427.535 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H29NO3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.08 Å3/Da / Density % sol: 40.78 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 25% PEG 3350, 0.3 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 PILATUS 6M / Detector: PIXEL / Date: Jul 31, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→87.52 Å / Num. obs: 9648 / % possible obs: 99.1 % / Redundancy: 3.2 % / Biso Wilson estimate: 93.58 Å2 / Rmerge(I) obs: 0.063 / Net I/σ(I): 14.3
Reflection shellResolution: 3→3.01 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.526 / Mean I/σ(I) obs: 2.3 / Num. measured all: 355 / Num. unique all: 107 / Rpim(I) all: 0.338 / Rrim(I) all: 0.627 / Net I/σ(I) obs: 2.3 / Rejects: 0 / % possible all: 99.1

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Processing

Software
NameVersionClassification
SCALAdata scaling
BUSTER-TNT2.11.4refinement
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 3→87.52 Å / Cor.coef. Fo:Fc: 0.8861 / Cor.coef. Fo:Fc free: 0.8386 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.474
RfactorNum. reflection% reflectionSelection details
Rfree0.2909 466 4.83 %RANDOM
Rwork0.2268 ---
obs0.2298 9646 99.11 %-
Displacement parametersBiso max: 144.21 Å2 / Biso mean: 75.83 Å2 / Biso min: 23.67 Å2
Baniso -1Baniso -2Baniso -3
1-24.6505 Å20 Å2-2.5279 Å2
2---23.3604 Å20 Å2
3----1.2901 Å2
Refine analyzeLuzzati coordinate error obs: 0.376 Å
Refinement stepCycle: final / Resolution: 3→87.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2940 0 64 6 3010
Biso mean--67.41 49.44 -
Num. residues----368
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeight
X-RAY DIFFRACTIONt_dihedral_angle_d1099SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes66HARMONIC2
X-RAY DIFFRACTIONt_gen_planes428HARMONIC5
X-RAY DIFFRACTIONt_it3059HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion392SEMIHARMONIC5
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_contact3628SEMIHARMONIC4
LS refinement shellResolution: 3→3.35 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2788 134 4.93 %
Rwork0.2154 2584 -
all0.2184 2718 -
obs--99.11 %

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