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- PDB-9bpx: Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Com... -

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Entry
Database: PDB / ID: 9bpx
TitleEstrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with (1'-(4-((1-butylpyrrolidin-3-yl)methoxy)phenyl)-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl)(phenyl)methanone
ComponentsEstrogen receptor
KeywordsTRANSCRIPTION / Estrogen / Alpha Helical Bundle / Breast Cancer
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 / nuclear estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / 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 / nuclear estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / epithelial cell development / negative regulation of smooth muscle cell apoptotic process / uterus development / mammary gland branching involved in pregnancy / vagina development / TFIIB-class transcription factor binding / steroid hormone receptor signaling pathway / androgen metabolic process / cellular response to estrogen stimulus / mammary gland alveolus development / estrogen response element binding / Mitochondrial unfolded protein response (UPRmt) / nuclear receptor-mediated steroid hormone signaling pathway / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / protein localization to chromatin / estrogen receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / steroid binding / 14-3-3 protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / TBP-class protein binding / nitric-oxide synthase regulator activity / positive regulation of nitric-oxide synthase activity / negative regulation of miRNA transcription / ESR-mediated signaling / positive regulation of DNA-binding transcription factor activity / transcription coregulator binding / transcription corepressor binding / nuclear estrogen receptor binding / negative regulation of DNA-binding transcription factor activity / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / transcription coactivator binding / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / nuclear receptor activity / positive regulation of fibroblast proliferation / male gonad development / 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 / ATPase binding / positive regulation of cytosolic calcium ion concentration / DNA-binding transcription activator activity, RNA polymerase II-specific / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of inflammatory response / 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 / Extra-nuclear estrogen signaling / calmodulin binding / chromatin remodeling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / 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 / 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 / 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
Similarity search - Domain/homology
: / HISTIDINE / Chem-TZI / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsYoung, K.Y. / Fanning, S.W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R37CA279341 United States
CitationJournal: Breast Cancer Res / Year: 2025
Title: Targeting unique ligand binding domain structural features downregulates DKK1 in Y537S ESR1 mutant breast cancer cells.
Authors: Young, K.S. / Hancock, G.R. / Fink, E.C. / Zigrossi, A. / Flowers, B. / Cooper, D.A. / Nguyen, V.T. / Martinez, M.C. / Mon, K.S. / Bosland, M. / Zak, D.R. / Runde, A.P. / Sharifi, M.N. / ...Authors: Young, K.S. / Hancock, G.R. / Fink, E.C. / Zigrossi, A. / Flowers, B. / Cooper, D.A. / Nguyen, V.T. / Martinez, M.C. / Mon, K.S. / Bosland, M. / Zak, D.R. / Runde, A.P. / Sharifi, M.N. / Kastrati, I. / Minh, D.D.L. / Kregel, S. / Fanning, S.W.
History
DepositionMay 8, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release

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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)61,2155
Polymers60,0322
Non-polymers1,1833
Water3,351186
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2850 Å2
ΔGint-8 kcal/mol
Surface area19800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.731, 58.294, 87.011
Angle α, β, γ (deg.)90.00, 103.52, 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: 30015.990 Da / Num. of mol.: 2
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-HIS / HISTIDINE


Type: L-peptide linking / Mass: 156.162 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H10N3O2
#3: Chemical ChemComp-TZI / [(1'R)-1'-(4-{[(3R)-1-(3-fluoropropyl)pyrrolidin-3-yl]methoxy}phenyl)-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl](phenyl)methanone


Mass: 514.630 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H35FN2O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-A1BV9 / [(1'R)-1'-(4-{[(3S)-1-(3-fluoropropyl)-2,3-dihydro-1H-pyrrol-3-yl]methoxy}phenyl)-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl](phenyl)methanone


Mass: 512.614 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H33FN2O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 186 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.09 Å3/Da / Density % sol: 41.13 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: PEG 3,350, MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 15, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 24826 / % possible obs: 98.1 % / Redundancy: 3.7 % / CC1/2: 0.999 / Rpim(I) all: 0.068 / Net I/σ(I): 1894.37
Reflection shellResolution: 2.2→2.24 Å / Num. unique obs: 1248 / CC1/2: 0.655

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→45.63 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 21.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2211 1137 4.77 %
Rwork0.1858 --
obs0.1875 23841 94.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→45.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3611 0 86 186 3883
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023833
X-RAY DIFFRACTIONf_angle_d0.5115198
X-RAY DIFFRACTIONf_dihedral_angle_d11.48517
X-RAY DIFFRACTIONf_chiral_restr0.032610
X-RAY DIFFRACTIONf_plane_restr0.004639
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.30.27931120.2332247X-RAY DIFFRACTION75
2.3-2.420.30381320.2152743X-RAY DIFFRACTION91
2.42-2.570.24481560.20272844X-RAY DIFFRACTION95
2.57-2.770.26671490.20822964X-RAY DIFFRACTION99
2.77-3.050.22471640.19232946X-RAY DIFFRACTION99
3.05-3.490.211280.18182977X-RAY DIFFRACTION98
3.49-4.40.19931320.15972999X-RAY DIFFRACTION98
4.4-45.630.19221640.18122984X-RAY DIFFRACTION97
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)
15.56883.7576-1.60825.8774-2.67563.10990.10350.18670.5449-0.13570.17070.6655-0.1332-0.2174-0.32060.28370.1104-0.02010.1833-0.02260.254-3.3868-16.181523.7159
23.42891.1316-1.98940.4955-1.04314.3317-0.03550.49640.0028-0.0465-0.00870.03730.0016-0.28530.04040.19390.06050.00050.2309-0.02320.22210.3715-22.910417.6258
37.5929-0.03271.00081.52750.94277.18050.0526-0.5605-0.53930.49320.08140.20520.4744-0.3001-0.0660.28040.04310.03190.26120.03490.244-2.667-28.282837.1851
42.24380.7592-0.77422.17-1.94625.323-0.0194-0.0049-0.1027-0.0363-0.0349-0.03330.17470.31830.07720.15570.051-0.02180.18530.01280.22869.5746-22.710826.2047
52.90371.1951.13374.15263.26442.2218-0.02280.36440.31-0.2755-0.002-0.1435-0.53290.17260.05370.29140.0001-0.00020.2160.10640.281117.0373-12.891515.2337
67.62653.46420.30635.74120.29942.0256-0.0682-0.0704-0.3991-0.1395-0.0697-0.32780.11280.05540.15140.23590.07660.00310.17960.01860.217513.7659-25.463426.497
76.7977-5.9545.74412.1501-7.75972.17160.22930.1031-0.5760.6377-0.01731.01390.7411-0.7876-0.33220.6188-0.1661-0.04130.9444-0.18980.4342-5.123-25.55018.2564
82.00041.9997-8.816720.06682.00020.0345-0.37460.90170.55540.02911.88-0.17210.2977-0.09830.51770.23850.39821.5712-0.40481.5353-13.0003-12.544.7115
94.8745-0.00342.06727.77011.64814.8875-0.1629-0.01940.58860.25140.0161-0.43040.07050.42080.15190.13970.03320.00730.36890.00090.379438.3707-32.188626.5943
101.10560.6299-1.90477.8541-1.30759.20150.32890.314-0.4679-0.0191.2046-0.59961.05790.5046-1.49350.8111-0.07420.04390.6938-0.25250.936731.5506-56.78617.9844
113.7237-0.7467-0.17197.12082.1125.1467-0.0896-0.1421-0.34590.54220.3114-0.39160.22590.4242-0.16320.20450.073-0.00530.22470.05770.202231.6002-41.387628.0777
123.4062-0.8980.76694.59240.19852.83780.19110.29960.112-0.07760.0097-0.14760.16830.0712-0.1320.17180.0801-0.01030.1880.01880.212627.8956-37.880721.5956
136.4552-3.48550.93593.1223-1.20651.25350.4981.0954-0.427-0.9415-0.53180.73481.1899-0.6328-0.00470.64120.1717-0.07210.9063-0.26680.447122.7366-45.96166.0234
143.28210.29391.51465.6021.79285.1620.16930.30290.0575-0.1714-0.0077-0.1321-0.1418-0.0198-0.11270.16930.11270.01340.24630.02830.238725.2642-30.136919.0669
153.41630.77180.33616.2259-0.872.8569-0.0671-0.03160.20360.1182-0.0395-0.2477-0.21670.18810.11120.10090.05040.00810.2226-0.00230.208624.758-23.307624.4258
162.2492-2.7806-0.8976.6271-3.91679.76970.66141.3184-0.7907-1.2428-0.3580.68320.5011-0.6687-0.40040.55530.0986-0.06980.4783-0.11420.432723.8812-48.889932.3275
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 306 through 341 )
2X-RAY DIFFRACTION2chain 'A' and (resid 342 through 394 )
3X-RAY DIFFRACTION3chain 'A' and (resid 395 through 420 )
4X-RAY DIFFRACTION4chain 'A' and (resid 421 through 465 )
5X-RAY DIFFRACTION5chain 'A' and (resid 466 through 496 )
6X-RAY DIFFRACTION6chain 'A' and (resid 497 through 526 )
7X-RAY DIFFRACTION7chain 'A' and (resid 527 through 549 )
8X-RAY DIFFRACTION8chain 'A' and (resid 550 through 550 )
9X-RAY DIFFRACTION9chain 'B' and (resid 306 through 331 )
10X-RAY DIFFRACTION10chain 'B' and (resid 332 through 341 )
11X-RAY DIFFRACTION11chain 'B' and (resid 342 through 371 )
12X-RAY DIFFRACTION12chain 'B' and (resid 372 through 407 )
13X-RAY DIFFRACTION13chain 'B' and (resid 408 through 420 )
14X-RAY DIFFRACTION14chain 'B' and (resid 421 through 469 )
15X-RAY DIFFRACTION15chain 'B' and (resid 470 through 525 )
16X-RAY DIFFRACTION16chain 'B' and (resid 526 through 546 )

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