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- PDB-8dv8: Estrogen Receptor Alpha Ligand Binding Domain in Complex with (6'... -

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Basic information

Entry
Database: PDB / ID: 8dv8
TitleEstrogen Receptor Alpha Ligand Binding Domain in Complex with (6'-hydroxy-1'-(4-((2-(1-propylpyrrolidin-3-yl)ethyl)thio)phenyl)-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 / 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 / TBP-class protein binding / negative regulation of miRNA transcription / 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 / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / 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-TZ3 / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 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 28, 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)59,0914
Polymers58,0662
Non-polymers1,0252
Water8,395466
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2840 Å2
ΔGint-11 kcal/mol
Surface area18200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.111, 58.130, 87.645
Angle α, β, γ (deg.)90.000, 102.790, 90.000
Int Tables number5
Space group name H-MC121
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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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-TZ3 / {(1'R)-6'-hydroxy-1'-[4-({[(3S)-1-propylpyrrolidin-3-yl]methyl}sulfanyl)phenyl]-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl}(phenyl)methanone


Mass: 512.705 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H36N2O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 466 / 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: 2.21 Å3/Da / Density % sol: 44.23 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: PEG 3350, MgCl2, pH 8.0

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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 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 54985 / % possible obs: 99.6 % / Redundancy: 3.7 % / Biso Wilson estimate: 14.82 Å2 / CC1/2: 0.996 / Net I/σ(I): 2033
Reflection shellResolution: 1.7→1.73 Å / Num. unique obs: 2693 / CC1/2: 0.876

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Processing

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

5ufx


Resolution: 1.7→41.41 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 21.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2109 2533 4.9 %
Rwork0.1867 49112 -
obs0.1878 51645 92.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 81.52 Å2 / Biso mean: 21.1119 Å2 / Biso min: 0.5 Å2
Refinement stepCycle: final / Resolution: 1.7→41.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3372 0 74 466 3912
Biso mean--0.5 31.34 -
Num. residues----426
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 18

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7-1.730.3667800.27791502158252
1.73-1.770.25681100.25651952206267
1.77-1.810.28521280.23652342247079
1.81-1.850.25951170.23622684280191
1.85-1.90.2631340.23552745287995
1.9-1.950.26951610.24212841300296
1.95-20.2521420.19962861300398
2-2.070.22721500.19762884303498
2.07-2.140.21321510.17782892304398
2.14-2.230.20341440.17462887303199
2.23-2.330.18431370.17052901303899
2.33-2.450.2031390.17272934307399
2.45-2.610.18751410.17272922306399
2.61-2.810.21441630.18612928309199
2.81-3.090.20521450.17729473092100
3.09-3.540.21730.177229003073100
3.54-4.460.17661530.15929693122100
4.46-41.410.19891650.19013021318699
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)
12.9216-1.05781.01625.97950.17046.5991-0.11910.34490.4876-0.4677-0.14050.4526-0.6691-0.28980.25560.21720.0367-0.0680.20060.02810.44581.98744.909211.038
22.9554-0.35910.58053.24830.15381.97390.0219-0.239-0.35470.2856-0.01940.13940.2361-0.0669-0.03120.0928-0.0760.03280.1317-0.01950.18377.8052-17.984221.2368
31.71410.3196-0.22182.0197-0.13292.20560.0641-0.01230.0259-0.137-0.07930.0885-0.0240.02660.0260.0647-0.03280.00750.0748-0.01540.078714.599-8.111411.5859
41.550.6356-0.69671.03140.34930.84180.2487-0.6464-0.09130.5444-0.3189-0.081-0.04570.30660.15910.3579-0.2480.02750.4815-0.00070.159813.7337-14.26134.9916
51.7158-0.64380.70614.6999-0.72472.66610.0098-0.4094-0.05650.82530.0349-0.1138-0.21460.0963-0.02050.2998-0.1567-0.00020.32930.01750.093618.9535-5.852232.7146
62.35060.13360.55284.32260.23341.8529-0.0840.19860.2575-0.1815-0.01610.2547-0.0334-0.18920.10020.0771-0.0296-0.02280.1258-0.00880.187813.03344.862114.1999
72.2772-0.79940.32016.1534-0.08491.1541-0.0002-0.2055-0.0060.2261-0.0460.0753-0.0093-0.08650.06260.0771-0.05050.01910.1231-0.00670.068221.01910.969423.1454
85.70460.61620.43936.22560.6516.7922-0.1192-0.0522-0.11420.01050.0119-0.0499-0.01910.02010.10640.1282-0.01760.02020.1115-0.02940.044114.3948-18.08246.8038
93.401-1.7727-0.68814.3050.87112.2242-0.1921-0.46380.33860.1790.2191-0.0292-0.19090.1446-0.03220.1138-0.0232-0.04040.07960.00590.109841.703615.656120.6288
101.8285-0.1155-0.2560.78710.08631.4919-0.0487-0.0006-0.1257-0.02270.0077-0.0080.02350.05680.02730.0619-0.021-0.00620.03810.00270.069742.55733.452819.2928
111.6223-0.50420.02491.36960.73292.4201-0.04240.0303-0.10080.0349-0.0620.0030.1273-0.24920.09530.0687-0.0534-0.00030.0659-0.01010.093631.84355.115116.9773
122.09530.17170.08761.49150.15161.925-0.0462-0.08470.14450.0264-0.03140.0738-0.143-0.13260.06410.0722-0.0274-0.0040.0809-0.00960.112525.85189.318521.5279
131.29280.36461.80571.15990.34392.87330.0446-0.1942-0.13590.2048-0.0182-0.08030.48420.1588-0.32390.55730.35310.00630.92290.08550.289644.6357-1.084832.7425
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 307 through 321 )A307 - 321
2X-RAY DIFFRACTION2chain 'A' and (resid 322 through 363 )A322 - 363
3X-RAY DIFFRACTION3chain 'A' and (resid 364 through 394 )A364 - 394
4X-RAY DIFFRACTION4chain 'A' and (resid 395 through 416 )A395 - 416
5X-RAY DIFFRACTION5chain 'A' and (resid 422 through 437 )A422 - 437
6X-RAY DIFFRACTION6chain 'A' and (resid 438 through 496 )A438 - 496
7X-RAY DIFFRACTION7chain 'A' and (resid 497 through 525 )A497 - 525
8X-RAY DIFFRACTION8chain 'A' and (resid 526 through 547 )A526 - 547
9X-RAY DIFFRACTION9chain 'B' and (resid 309 through 338 )B309 - 338
10X-RAY DIFFRACTION10chain 'B' and (resid 339 through 420 )B339 - 420
11X-RAY DIFFRACTION11chain 'B' and (resid 421 through 465 )B421 - 465
12X-RAY DIFFRACTION12chain 'B' and (resid 466 through 525 )B466 - 525
13X-RAY DIFFRACTION13chain 'B' and (resid 526 through 544 )B526 - 544

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