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- PDB-8du6: Estrogen Receptor Alpha Ligand Binding Domain in Complex with (1'... -

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Entry
Database: PDB / ID: 8du6
TitleEstrogen Receptor Alpha Ligand Binding Domain in Complex with (1'-(4-((1-ethylazetidin-3-yl)oxy)phenyl)-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl)(phenyl)methanone
ComponentsEstrogen receptor
KeywordsTRANSCRIPTION / Antiestrogen / breast cancer / alpha helical bundle / estrogen 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 / androgen metabolic process / TFIIB-class transcription factor binding / steroid hormone mediated signaling pathway / mammary gland alveolus development / intracellular estrogen receptor signaling pathway / cellular response to estrogen stimulus / estrogen response element binding / : / intracellular steroid hormone receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / protein localization to chromatin / TBP-class protein binding / steroid binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / 14-3-3 protein binding / nitric-oxide synthase regulator activity / ESR-mediated signaling / transcription corepressor binding / negative regulation of miRNA transcription / cellular response to estradiol stimulus / transcription coregulator binding / stem cell differentiation / nuclear estrogen receptor binding / positive regulation of nitric-oxide synthase activity / SUMOylation of intracellular receptors / euchromatin / transcription coactivator binding / negative regulation of DNA-binding transcription factor activity / beta-catenin binding / Nuclear Receptor transcription pathway / positive regulation of DNA-binding transcription factor activity / response to estrogen / male gonad development / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / positive regulation of nitric oxide biosynthetic process / positive regulation of fibroblast proliferation / Ovarian tumor domain proteases / sequence-specific double-stranded DNA binding / response to estradiol / PIP3 activates AKT signaling / phospholipase C-activating G protein-coupled receptor signaling pathway / ATPase binding / positive regulation of cytosolic calcium ion concentration / 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 / chromatin / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of DNA-templated transcription / Golgi apparatus / negative regulation of transcription by RNA polymerase II / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / membrane / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
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 / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) ...Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related 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
Similarity search - Domain/homology
Chem-TQF / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsHancock, G.R. / Young, K.S. / Hosfield, D.J. / Joiner, C. / Sullivan, E.A. / Yildz, Y. / Laine, M. / Greene, G.L. / Fanning, S.W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: NPJ Breast Cancer / Year: 2022
Title: Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells.
Authors: Hancock, G.R. / Young, K.S. / Hosfield, D.J. / Joiner, C. / Sullivan, E.A. / Yildiz, Y. / Laine, M. / Greene, G.L. / Fanning, S.W.
History
DepositionJul 27, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._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 / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 25, 2023Group: 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: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,9754
Polymers58,0662
Non-polymers9092
Water3,585199
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2940 Å2
ΔGint-14 kcal/mol
Surface area18670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.280, 58.370, 87.657
Angle α, β, γ (deg.)90.00, 103.12, 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: 29033.018 Da / Num. of mol.: 2 / Mutation: C381S, C417S, C530S, L536S
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-TQF / [(1'R)-1'-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl](phenyl)methanone


Mass: 454.560 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H30N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 199 / 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: 2.19 Å3/Da / Density % sol: 43.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: PEG 3,350, MgCl2, HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 28464 / % possible obs: 95.6 % / Redundancy: 3.3 % / CC1/2: 0.985 / Rpim(I) all: 0.087 / Net I/σ(I): 0.048
Reflection shellResolution: 2.1→2.14 Å / Num. unique obs: 1253 / CC1/2: 0.558

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5UFX

5ufx


Resolution: 2.1→49.81 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 24.33 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.239 1243 4.95 %
Rwork0.19 --
obs0.192 25113 84.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.92 Å2
Refinement stepCycle: LAST / Resolution: 2.1→49.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3563 0 68 199 3830
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.180.3373750.22051794X-RAY DIFFRACTION57
2.18-2.280.24911140.20372116X-RAY DIFFRACTION68
2.28-2.40.25661280.19632359X-RAY DIFFRACTION76
2.4-2.550.23691370.1942567X-RAY DIFFRACTION82
2.55-2.740.25391610.2012661X-RAY DIFFRACTION86
2.75-3.020.26261310.19582874X-RAY DIFFRACTION91
3.02-3.460.22631730.19383106X-RAY DIFFRACTION99
3.46-4.350.2141660.16843146X-RAY DIFFRACTION100
4.36-49.810.2381580.19123247X-RAY DIFFRACTION100
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)
18.0589-3.4680.30088.42492.09227.1801-0.4146-0.59910.83720.24970.4099-0.155-1.3397-0.0623-0.03360.535-0.027-0.00470.2444-0.10290.3408-18.855122.281425.1696
22.7156-2.711-1.72429.40044.63424.84010.09210.0835-0.11460.40260.1682-0.67320.55670.1243-0.22040.167-0.047-0.05550.2812-0.01050.3582-0.50653.882914.0888
35.9757-5.0266-3.4244.97873.13994.65940.0015-0.49890.07050.00490.1868-0.2455-0.17020.4451-0.14350.1483-0.09340.00630.21460.0540.1484-4.5533.757522.369
42.5746-0.7929-1.09361.26231.01995.41570.0346-0.0423-0.14740.00030.00510.02470.12380.2659-0.01920.1379-0.0632-0.03130.12210.00120.1645-11.64672.387217.7619
54.8497-4.0061-1.03363.43490.09154.880.22160.3468-0.3409-0.1419-0.48830.30170.2421-0.01420.19730.2701-0.0796-0.06390.2415-0.02180.1929-17.3216-0.66687.0331
63.1449-1.0723-0.23121.83782.05216.3147-0.0266-0.3156-0.0738-0.0396-0.08560.14490.41250.002-0.05950.1645-0.0546-0.00790.1434-0.00540.189-21.37918.584722.1983
73.0105-0.5395-0.11782.1566-0.46665.87880.1563-0.29090.34260.3480.02690.2092-0.66230.0905-0.08530.292-0.04890.03050.161-0.0960.2634-27.541114.529127.5016
85.8691-5.18862.60964.6415-2.29112.35650.05560.5379-0.09220.2523-0.3448-0.0521-0.0310.05330.21440.1945-0.04880.01470.2037-0.00940.3023-23.37861.278716.0428
91.494-0.3479-0.50498.99754.52986.2299-0.143-0.799-0.06881.00690.6543-0.7950.72351.0815-0.45110.38150.134-0.04740.78410.06980.2907-5.654-0.658233.8652
102.46150.1040.17665.9392-0.72842.43530.0757-0.012-0.22690.0891-0.02670.38940.0569-0.3817-0.07210.091-0.03050.02980.2157-0.03170.2205-44.8097-11.668317.4496
111.92950.2594-0.05962.4494-0.21153.98410.1021-0.4378-0.1560.3804-0.1627-0.14250.14740.26680.0490.143-0.0831-0.00920.2632-0.00340.1655-36.1856-10.133824.6915
121.55280.75611.22895.55570.25035.2062-0.1580.2090.1962-0.31160.12270.1886-0.08430.0362-0.01310.11730.0037-0.04040.18140.00990.2332-38.35653.544413.0049
131.23490.63580.20254.27280.98761.34150.0894-0.0401-0.03390.1528-0.165-0.22760.0813-0.020.06090.1269-0.02170.02790.24790.01510.205-32.0754-7.14618.404
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 308 THROUGH 321 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 322 THROUGH 341 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 342 THROUGH 363 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 364 THROUGH 420 )
5X-RAY DIFFRACTION5CHAIN 'A' AND (RESID 421 THROUGH 437 )
6X-RAY DIFFRACTION6CHAIN 'A' AND (RESID 438 THROUGH 465 )
7X-RAY DIFFRACTION7CHAIN 'A' AND (RESID 466 THROUGH 496 )
8X-RAY DIFFRACTION8CHAIN 'A' AND (RESID 497 THROUGH 528 )
9X-RAY DIFFRACTION9CHAIN 'A' AND (RESID 529 THROUGH 547 )
10X-RAY DIFFRACTION10CHAIN 'B' AND (RESID 307 THROUGH 363 )
11X-RAY DIFFRACTION11CHAIN 'B' AND (RESID 364 THROUGH 438 )
12X-RAY DIFFRACTION12CHAIN 'B' AND (RESID 439 THROUGH 496 )
13X-RAY DIFFRACTION13CHAIN 'B' AND (RESID 497 THROUGH 545 )

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