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- PDB-8dv5: Estrogen Receptor Alpha Ligand Binding Domain in Complex with (6'... -

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Entry
Database: PDB / ID: 8dv5
TitleEstrogen Receptor Alpha Ligand Binding Domain in Complex with (6'-hydroxy-1'-(4-((1-pentylpyrrolidin-3-yl)methoxy)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 / 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-TX9 / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 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)59,1154
Polymers58,0662
Non-polymers1,0492
Water5,423301
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2960 Å2
ΔGint-13 kcal/mol
Surface area19060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.927, 57.340, 87.144
Angle α, β, γ (deg.)90.000, 103.090, 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-TX9 / [(1'R)-6'-hydroxy-1'-(4-{[(3S)-1-pentylpyrrolidin-3-yl]methoxy}phenyl)-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl](phenyl)methanone


Mass: 524.693 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H40N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 301 / 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: 2.14 Å3/Da / Density % sol: 42.41 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: PEG 3,350, MgCl2, HEPES pH 6.5

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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: Sep 21, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 41967 / % possible obs: 99.8 % / Redundancy: 3.7 % / Biso Wilson estimate: 20.22 Å2 / CC1/2: 0.999 / Net I/σ(I): 1085
Reflection shellResolution: 1.85→1.88 Å / Num. unique obs: 2022 / CC1/2: 0.547

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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: 1.85→45.15 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 22.18 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2131 1850 4.85 %
Rwork0.1845 36275 -
obs0.1859 38125 90.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 78.68 Å2 / Biso mean: 25.742 Å2 / Biso min: 5.54 Å2
Refinement stepCycle: final / Resolution: 1.85→45.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3566 0 78 301 3945
Biso mean--22.57 33.02 -
Num. residues----454
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.85-1.90.3413870.27411479156649
1.9-1.960.2633990.24271947204664
1.96-2.020.26811250.21712390251578
2.02-2.090.25351320.21132755288790
2.09-2.170.25461490.19323008315799
2.17-2.270.23391620.182230463208100
2.27-2.390.24861460.177830793225100
2.39-2.540.20411660.175530693235100
2.54-2.740.23091520.179430813233100
2.74-3.020.21871640.176230573221100
3.02-3.450.20341430.177731173260100
3.45-4.350.16791570.160330903247100
4.35-45.150.19461680.196731573325100
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)
12.8761-1.103-0.4122.20160.03324.2917-0.1540.8662-0.0351-0.89980.06790.2950.0883-0.16670.12030.31440.2030.03050.4053-0.03060.142528.0792-41.82867.5247
23.43482.33170.66378.46931.13263.2681-0.04360.2905-0.0893-1.2124-0.3040.1187-0.3097-0.27570.27710.24330.1305-0.03660.3133-0.02370.09323.0915-33.10149.9118
32.0002-0.72910.66384.07470.22834.90380.099-0.00920.12450.1538-0.01530.0908-0.1242-0.1388-0.01760.09110.0381-0.01280.07430.0260.15727.0566-28.098527.248
41.83110.2059-0.32055.6849-2.96525.20370.1022-0.18320.29940.53560.04950.0354-0.36980.2465-0.01150.1424-0.0085-0.05170.1444-0.03750.16628.7728-20.267532.0498
53.49781.83150.03186.4167-0.40741.76340.08490.1247-0.3362-0.2997-0.1447-0.01820.052-0.1207-0.01520.07870.0732-0.00110.1745-0.00920.133220.2157-29.127519.3969
67.33551.9291-0.23759.18781.03146.5876-0.01450.15-0.5443-0.0057-0.1559-0.15920.1394-0.03920.15730.17710.00980.00350.11590.02890.104626.2767-46.951935.037
77.89083.5253-1.69474.407-0.26776.28870.14840.59511.2631-0.15660.44580.4525-1.5320.1138-0.40910.45780.0420.09230.20440.15860.41087.8667-5.505917.5353
80.1679-0.530.31263.2464-0.65450.65880.2508-0.1837-0.00350.30490.05961.16030.2255-0.9358-0.28380.09410.0286-0.03420.29710.01150.3829-10.8152-22.341429.6804
94.45772.3772-1.76263.3265-1.43673.18830.01860.30940.05170.0603-0.05820.113-0.0689-0.2420.03110.08760.0714-0.00760.1636-0.00350.1261-6.0682-24.951121.177
102.2490.2865-1.14491.643-0.29484.1646-0.05830.39940.0263-0.0940.0867-0.0228-0.0611-0.138-0.04620.07210.0273-0.01920.13420.01260.10524.7359-22.90515.9372
113.2731-0.52880.07692.0046-0.12052.70380.1282-0.3708-0.390.1712-0.09030.10070.174-0.1922-0.05550.17050.0055-0.01420.1540.04140.11811.5178-28.316736.3842
122.97181.60960.85572.0701-1.91424.5885-0.03950.2361-0.0646-0.06170.1258-0.09070.12850.3749-0.09990.09990.0436-0.00130.10550.0110.12911.3087-18.899420.3075
132.52051.36990.44982.6391.16776.13520.18880.33680.4795-0.2390.066-0.2354-0.6003-0.1236-0.15240.20820.06350.03050.1580.0790.230217.2882-12.818915.2765
145.08053.57810.9775.65441.08061.53780.1531-0.114-0.14380.2134-0.14710.11650.06760.0212-0.01810.13570.0590.02430.11560.01270.112513.8728-25.615326.4799
150.884-0.76780.64333.9456-3.63164.2785-0.25170.8028-0.4293-0.61120.59420.38280.4375-0.9299-0.25270.3777-0.1581-0.03960.86160.00140.232-3.7571-28.31779.2938
163.22581.41211.59739.36193.77965.2215-0.24620.15710.25290.43950.1907-1.0903-0.36350.4732-0.05020.1871-0.0515-0.07420.18650.02120.29540.1113-23.511230.7521
174.88653.11361.89487.31762.57135.1994-0.02790.3474-0.4663-1.04770.1527-0.26140.2763-0.2485-0.16370.27490.1029-0.00880.2720.05050.212934.8754-47.842815.2814
182.0440.36850.62986.03972.22474.11030.0293-0.0212-0.3123-0.0869-0.0633-0.06930.23860.1984-0.01030.08460.05450.00850.14010.01320.143231.893-44.385424.6235
192.202-0.6308-0.752.09760.39564.4529-0.0538-0.0003-0.02070.1386-0.07460.02850.06170.07580.09590.08340.0295-0.00840.0520.00820.096826.9489-36.026830.2024
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 395 through 420 )B395 - 420
2X-RAY DIFFRACTION2chain 'B' and (resid 421 through 438 )B421 - 438
3X-RAY DIFFRACTION3chain 'B' and (resid 439 through 466 )B439 - 466
4X-RAY DIFFRACTION4chain 'B' and (resid 467 through 496 )B467 - 496
5X-RAY DIFFRACTION5chain 'B' and (resid 497 through 528 )B497 - 528
6X-RAY DIFFRACTION6chain 'B' and (resid 533 through 545 )B529 - 545
7X-RAY DIFFRACTION7chain 'A' and (resid 309 through 322 )A309 - 322
8X-RAY DIFFRACTION8chain 'A' and (resid 323 through 338 )A323 - 338
9X-RAY DIFFRACTION9chain 'A' and (resid 339 through 363 )A339 - 363
10X-RAY DIFFRACTION10chain 'A' and (resid 364 through 395 )A364 - 395
11X-RAY DIFFRACTION11chain 'A' and (resid 396 through 437 )A396 - 437
12X-RAY DIFFRACTION12chain 'A' and (resid 438 through 465 )A438 - 465
13X-RAY DIFFRACTION13chain 'A' and (resid 466 through 496 )A466 - 496
14X-RAY DIFFRACTION14chain 'A' and (resid 497 through 527 )A497 - 527
15X-RAY DIFFRACTION15chain 'A' and (resid 528 through 547 )A528 - 547
16X-RAY DIFFRACTION16chain 'B' and (resid 309 through 321 )B309 - 321
17X-RAY DIFFRACTION17chain 'B' and (resid 322 through 341 )B322 - 341
18X-RAY DIFFRACTION18chain 'B' and (resid 342 through 363 )B342 - 363
19X-RAY DIFFRACTION19chain 'B' and (resid 364 through 394 )B364 - 394

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