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

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Basic information

Entry
Database: PDB / ID: 8duk
TitleEstrogen Receptor Alpha Ligand Binding Domain in Complex with (6'-hydroxy-1'-(4-(2-(methylamino)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 / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of branching involved in prostate gland morphogenesis / prostate epithelial cord elongation / 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 ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of branching involved in prostate gland morphogenesis / prostate epithelial cord elongation / 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 proliferation involved in mammary gland duct elongation / epithelial cell development / vagina development / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / TFIIB-class transcription factor binding / androgen metabolic process / steroid hormone receptor signaling pathway / mammary gland alveolus development / 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 / 14-3-3 protein binding / protein localization to chromatin / estrogen receptor signaling pathway / steroid binding / nitric-oxide synthase regulator activity / TBP-class protein 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 / positive regulation of DNA-binding transcription factor activity / SUMOylation of intracellular receptors / euchromatin / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / nuclear receptor activity / Regulation of RUNX2 expression and activity / positive regulation of fibroblast proliferation / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / phospholipase C-activating G protein-coupled receptor signaling pathway / ATPase binding / regulation of inflammatory response / positive regulation of cytosolic calcium ion concentration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / fibroblast proliferation / 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 / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / 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 / 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 / identical protein binding / membrane / 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 ...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-TW6 / 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 27, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Jul 17, 2024Group: 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

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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
C: Estrogen receptor
D: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,8468
Polymers116,1324
Non-polymers1,7144
Water11,818656
1
A: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,9234
Polymers58,0662
Non-polymers8572
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2930 Å2
ΔGint-17 kcal/mol
Surface area20600 Å2
MethodPISA
2
C: Estrogen receptor
D: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,9234
Polymers58,0662
Non-polymers8572
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2890 Å2
ΔGint-17 kcal/mol
Surface area20720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.031, 57.665, 174.519
Angle α, β, γ (deg.)90.000, 102.510, 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.: 4 / 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-TW6 / [(1'R)-6'-hydroxy-1'-{4-[2-(methylamino)ethoxy]phenyl}-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl](phenyl)methanone


Mass: 428.523 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H28N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 656 / 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: 43 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: PEG 8,000, MgCl2, HEPES 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 18, 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: 106232 / % possible obs: 98 % / Redundancy: 3.4 % / CC1/2: 0.998 / Rpim(I) all: 0.05 / Net I/σ(I): 208.37
Reflection shellResolution: 1.7→1.73 Å / Num. unique obs: 5068 / CC1/2: 0.624

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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: 1.7→49.91 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 40 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2684 5182 4.98 %
Rwork0.2311 98925 -
obs0.2329 104107 95.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 84.57 Å2 / Biso mean: 20.0932 Å2 / Biso min: 2.99 Å2
Refinement stepCycle: final / Resolution: 1.7→49.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7276 0 128 656 8060
Biso mean--17.6 27.71 -
Num. residues----928
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7-1.720.39211470.36242689283679
1.72-1.740.3681540.34682916307087
1.74-1.760.3641850.34263079326490
1.76-1.790.36681810.32463077325891
1.79-1.810.38431680.31683117328592
1.81-1.830.37421740.29543243341794
1.83-1.860.32981820.28433232341494
1.86-1.890.29511700.26893256342695
1.89-1.920.2981520.27143256340896
1.92-1.950.28181900.25813303349396
1.95-1.980.28851590.25253306346597
1.98-2.020.27631830.24883335351897
2.02-2.060.27281610.25413358351998
2.06-2.10.27541530.24783361351498
2.1-2.150.26241900.24343343353398
2.15-2.20.2861830.21933354353799
2.2-2.250.25291990.21413398359799
2.25-2.310.27511640.21023371353598
2.31-2.380.24981760.20763380355699
2.38-2.460.26691530.20473432358599
2.46-2.540.26831790.20263414359399
2.54-2.650.28141620.20533400356298
2.65-2.770.24061870.21263367355499
2.77-2.910.21622090.20083376358598
2.91-3.090.26231470.19913427357498
3.09-3.330.21551480.20463411355998
3.33-3.670.23181730.20093462363598
3.67-4.20.22831950.18813394358998
4.2-5.290.23191670.2053462362998
5.29-49.910.26371910.24423406359795
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)
10.8367-0.1438-0.38580.8827-0.11661.7610.0057-0.1305-0.03530.1698-0.0564-0.0542-0.07520.0450.0120.2944-0.1337-0.07360.18830.1377-0.0405-36.4988-8.840523.7189
20.8952-0.00550.08261.57960.77660.7016-0.0150.11470.1272-0.1531-0.0030.1763-0.0828-0.12560.09750.19390.0241-0.10.1755-0.03210.0794-37.30954.111312.715
31.10950.28410.21542.46750.78181.3530.0843-0.0576-0.19860.0630.0466-0.15060.16930.0217-0.10770.1481-0.00650.03470.2084-0.0270.1078-32.5102-7.711816.1033
43.91282.365-1.50982.9609-1.37691.7961-0.08930.15040.1473-0.19040.02040.0124-0.1993-0.01330.03220.11210.0266-0.0180.06040.04140.1667-8.341717.102263.6926
50.4847-0.3042-0.10310.5729-0.04160.59580.00640.11430.0191-0.0634-0.02110.09310.0103-0.0624-0.0918-0.08850.1363-0.1075-0.1690.12870.0454-11.06433.583662.389
62.2189-0.58920.4150.27720.31411.56940.0401-0.1866-0.40890.1156-0.02910.04890.2227-0.0262-0.05580.0103-0.0052-0.11430.07450.01690.163-11.8750.023880.015
71.51191.0159-0.10444.765-0.36262.47870.009-0.0686-0.11130.0617-0.0298-0.04820.141-0.0154-0.01240.05510.003-0.05110.07610.11770.1384-1.97770.278878.1973
80.4711-0.08930.30410.6212-0.73141.27720.02450.0214-0.0856-0.1053-0.0428-0.0330.09340.0383-0.01280.06270.017-0.10370.00480.05710.22021.96949.192762.8215
91.15980.57770.97561.18311.48024.51790.05620.19760.135-0.09280.0345-0.1450.01570.0312-0.09370.14080.0525-0.00120.02110.01570.16427.949415.069957.4292
100.58690.37860.04150.92650.18670.3764-0.0353-0.0169-0.01940.0415-0.05080.01210.0440.0548-0.0257-0.2092-0.01780.1909-0.14610.1637-0.01173.89282.201469.0604
111.49150.0193-0.12681.1099-0.5591.70780.24490.4431-0.245-0.3357-0.30010.10930.1287-0.08870.0640.3259-0.0704-0.00390.641-0.06430.1957-14.6421.127750.7605
121.360.0929-0.07741.4034-0.3850.84330.0018-0.06810.22280.0622-0.0157-0.0718-0.09710.0540.02490.01360.08220.00630.0850.0397-0.128725.9113-9.659568.6995
130.6045-0.2401-0.07770.7588-0.08440.64870.07430.25240.0082-0.2698-0.09350.0025-0.0482-0.0117-0.02340.00730.0830.03770.03460.1741-0.042717.6159-8.835461.5523
140.6043-0.27430.03420.49250.04310.59880.0014-0.03190.10930.04350.0162-0.03460.0106-0.0015-0.0208-0.1220.07630.15870.0556-0.0390.181618.41164.240572.5314
150.4202-0.11170.10190.8232-0.32190.4356-0.0153-0.04710.0405-0.0371-0.07880.04940.04310.04560.0009-0.0380.0861-0.0214-0.0156-0.0686-0.01413.7416-7.781269.5954
161.9811-1.2381-0.13551.7448-0.44571.27030.0084-0.10190.1372-0.0092-0.015-0.17440.00030.233-0.00440.1421-0.0544-0.02890.24890.02350.102-4.99888.321119.9399
171.6570.33390.20750.9089-0.25951.9247-0.09080.0587-0.1982-0.11760.0287-0.02410.02740.05620.07350.14170.0274-0.00260.207-0.00060.0062-11.30142.989617.7417
180.722-0.40150.02851.02030.39461.4560.07940.0053-0.0661-0.03430.06260.11230.1539-0.09940.01570.1483-0.08380.02840.19690.0648-0.0438-19.1985.516715.8535
190.7659-0.1270.51192.2236-2.23935.43810.0285-0.08270.09970.05620.05520.0282-0.1045-0.0516-0.0360.17980.0416-0.01460.2433-0.07350.0611-26.814915.179527.6782
200.9310.0280.43890.5690.03591.26010.0061-0.2049-0.10140.08870.052-0.13460.08490.1836-0.09220.2108-0.0161-0.07770.27290.08590.1289-16.01992.008323.053
212.00490.187-0.26814.0750.28621.8104-0.020.0623-0.1086-0.0616-0.060.14660.0007-0.20750.07840.0757-0.0266-0.02730.1538-0.00340.2264-44.8589-9.612816.5902
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 364 through 437 )B364 - 437
2X-RAY DIFFRACTION2chain 'B' and (resid 438 through 496 )B438 - 496
3X-RAY DIFFRACTION3chain 'B' and (resid 497 through 549 )B497 - 549
4X-RAY DIFFRACTION4chain 'C' and (resid 308 through 331 )C308 - 331
5X-RAY DIFFRACTION5chain 'C' and (resid 332 through 395 )C332 - 395
6X-RAY DIFFRACTION6chain 'C' and (resid 396 through 420 )C396 - 420
7X-RAY DIFFRACTION7chain 'C' and (resid 421 through 437 )C421 - 437
8X-RAY DIFFRACTION8chain 'C' and (resid 438 through 465 )C438 - 465
9X-RAY DIFFRACTION9chain 'C' and (resid 466 through 496 )C466 - 496
10X-RAY DIFFRACTION10chain 'C' and (resid 497 through 528 )C497 - 528
11X-RAY DIFFRACTION11chain 'C' and (resid 529 through 550 )C529 - 550
12X-RAY DIFFRACTION12chain 'D' and (resid 306 through 363 )D306 - 363
13X-RAY DIFFRACTION13chain 'D' and (resid 364 through 437 )D364 - 437
14X-RAY DIFFRACTION14chain 'D' and (resid 438 through 496 )D438 - 496
15X-RAY DIFFRACTION15chain 'D' and (resid 497 through 550 )D497 - 550
16X-RAY DIFFRACTION16chain 'A' and (resid 308 through 363 )A308 - 363
17X-RAY DIFFRACTION17chain 'A' and (resid 364 through 420 )A364 - 420
18X-RAY DIFFRACTION18chain 'A' and (resid 421 through 465 )A421 - 465
19X-RAY DIFFRACTION19chain 'A' and (resid 466 through 496 )A466 - 496
20X-RAY DIFFRACTION20chain 'A' and (resid 497 through 550 )A497 - 550
21X-RAY DIFFRACTION21chain 'B' and (resid 306 through 363 )B306 - 363

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