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

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Basic information

Entry
Database: PDB / ID: 8duh
TitleEstrogen Receptor Alpha Ligand Binding Domain in Complex with (6'-hydroxy-1'-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethoxy)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 / 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-TVL / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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)59,0314
Polymers58,0662
Non-polymers9652
Water5,206289
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2830 Å2
ΔGint-11 kcal/mol
Surface area18830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.720, 57.283, 87.524
Angle α, β, γ (deg.)90.000, 103.490, 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: 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-TVL / [(1'R)-6'-hydroxy-1'-(4-{2-[(2R)-2-methylpyrrolidin-1-yl]ethoxy}phenyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl](phenyl)methanone


Mass: 482.613 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H34N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 289 / 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: 2.16 Å3/Da / Density % sol: 42.95 %
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 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 37736 / % possible obs: 97.4 % / Redundancy: 3.3 % / CC1/2: 0.991 / Rpim(I) all: 0.06 / Net I/σ(I): 4493
Reflection shellResolution: 1.9→1.93 Å / Num. unique obs: 1576 / CC1/2: 0.502

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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: 1.9→45.26 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.33 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2351 1586 5.01 %
Rwork0.1856 30081 -
obs0.1881 31667 81.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 96.55 Å2 / Biso mean: 26.2141 Å2 / Biso min: 1.3 Å2
Refinement stepCycle: final / Resolution: 1.9→45.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3506 0 72 289 3867
Biso mean--20.76 32.24 -
Num. residues----449
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.9-1.960.3729580.21841207126536
1.96-2.030.2571890.22151732182152
2.03-2.110.27481070.21862100220763
2.11-2.210.23451300.19292410254072
2.21-2.330.26311430.18632754289782
2.33-2.470.25231620.18453018318090
2.47-2.660.23511980.18373333353199
2.66-2.930.24581830.191233773560100
2.93-3.360.2341700.184233783548100
3.36-4.230.19971770.16793367354499
4.23-45.260.23131690.18743405357498
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)
13.9144-1.9826-0.59372.97341.24173.25770.0749-0.22060.1732-0.1105-0.0067-0.1957-0.07260.167-0.11530.0847-0.0840.01570.09250.00770.129546.41635.68918.9495
22.22070.0293-0.59920.8797-0.03482.8185-0.0277-0.0655-0.1108-0.0481-0.0102-0.00850.09810.06840.01370.0767-0.0211-0.0130.0459-0.00480.083439.77410.578217.7179
34.7848-2.5621-0.14152.2109-1.20423.89130.31880.2456-0.6124-0.6835-0.38670.27320.3478-0.07020.06420.2279-0.051-0.02290.1229-0.02070.149634.2918-2.56616.9148
42.3265-0.0324-0.21382.0788-0.28844.1590.003-0.29780.27410.13-0.02430.1655-0.15090.05040.01030.1109-0.0221-0.01020.1285-0.05040.14126.811710.184924.6607
54.9147-0.55450.02982.20130.94012.5488-0.04-0.3974-0.53120.19730.12320.12840.29440.1209-0.00420.1579-0.05820.04610.16170.02520.074732.1328-1.16920.2442
64.2141.27360.94759.112-4.34128.1665-0.06910.12130.2718-0.47480.12891.4161-0.464-0.6214-0.04540.1950.0182-0.07390.1849-0.03980.37011.24822.387811.4764
71.95410.41530.26583.416-0.68412.3710.0267-0.0582-0.33490.3206-0.1421-0.12390.0957-0.02520.0260.1255-0.05440.02450.0958-0.0130.19118.2661-19.058520.4455
81.67140.50570.00942.3547-0.12742.84870.0004-0.00450.0303-0.2025-0.0206-0.080.0160.01920.04380.1094-0.02850.02390.0586-0.0140.103614.2447-10.283812.2562
93.09050.31810.69332.3745-0.18471.13840.246-0.92530.00041.0441-0.32470.1679-0.1550.20450.05210.381-0.1844-0.02380.4770.01390.09813.2834-16.09835.2869
103.9284-3.85830.02568.2713-0.83453.6913-0.193-0.66060.19631.0782-0.096-0.2592-0.14410.05370.13750.2858-0.1169-0.00320.4277-0.06360.142918.0836-6.987732.4445
112.59361.51052.14465.2961-1.17915.37950.10050.03530.2302-0.3047-0.1790.024-0.4468-0.00120.11310.1276-0.08830.01670.1072-0.03230.176913.7418-2.333615.9972
123.6729-1.4222-1.27447.85994.31116.5272-0.00540.05180.6285-0.37340.09860.1208-0.1737-0.14010.01980.0931-0.0049-0.04760.14340.00650.232610.69667.484313.2055
134.7614-3.2530.64862.4939-0.67241.6352-0.1031-0.2001-0.08830.5806-0.01390.1381-0.0039-0.00080.0760.1125-0.05310.02920.1708-0.01640.121721.064-2.557222.8755
143.7064-2.0231-1.65248.5191-3.0913.0756-0.04510.017-0.2931-0.0219-0.08110.2352-0.1302-0.0640.13880.1718-0.02180.00330.1653-0.05110.085913.4401-20.69826.5412
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 309 through 363 )A309 - 363
2X-RAY DIFFRACTION2chain 'A' and (resid 364 through 420 )A364 - 420
3X-RAY DIFFRACTION3chain 'A' and (resid 421 through 437 )A421 - 437
4X-RAY DIFFRACTION4chain 'A' and (resid 438 through 496 )A438 - 496
5X-RAY DIFFRACTION5chain 'A' and (resid 497 through 544 )A497 - 544
6X-RAY DIFFRACTION6chain 'B' and (resid 308 through 321 )B308 - 321
7X-RAY DIFFRACTION7chain 'B' and (resid 322 through 363 )B322 - 363
8X-RAY DIFFRACTION8chain 'B' and (resid 364 through 394 )B364 - 394
9X-RAY DIFFRACTION9chain 'B' and (resid 395 through 420 )B395 - 420
10X-RAY DIFFRACTION10chain 'B' and (resid 421 through 438 )B421 - 438
11X-RAY DIFFRACTION11chain 'B' and (resid 439 through 472 )B439 - 472
12X-RAY DIFFRACTION12chain 'B' and (resid 473 through 496 )B473 - 496
13X-RAY DIFFRACTION13chain 'B' and (resid 497 through 527 )B497 - 527
14X-RAY DIFFRACTION14chain 'B' and (resid 528 through 547 )B528 - 547

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