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- PDB-4xi3: Estrogen Receptor Alpha Ligand Binding Domain in Complex with Baz... -

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Basic information

Entry
Database: PDB / ID: 4xi3
TitleEstrogen Receptor Alpha Ligand Binding Domain in Complex with Bazedoxifene
ComponentsEstrogen receptor
KeywordsSIGNALING PROTEIN / Estrogen Receptor / SERM / Bazedoxifene / Breast Cancer / Nuclear Hormone 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 / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / vagina 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 / Nuclear Receptor transcription pathway / beta-catenin binding / response to estrogen / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / male gonad development / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of fibroblast proliferation / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / ATPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / regulation of inflammatory response / 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 / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor ...Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / 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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Bazedoxifene / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.491 Å
AuthorsFanning, S.W. / Mayne, C.G. / Toy, W. / Carlson, K. / Greene, B. / Nowak, J. / Walter, R. / Panchamukhi, S. / Tajhorshid, E. / Nettles, K.W. ...Fanning, S.W. / Mayne, C.G. / Toy, W. / Carlson, K. / Greene, B. / Nowak, J. / Walter, R. / Panchamukhi, S. / Tajhorshid, E. / Nettles, K.W. / Chandarlapaty, S. / Katzenellenbogen, J. / Greene, G.L.
Funding support United States, 1items
OrganizationGrant numberCountry
Department of Defense (DOD, United States)BC131458P1 United States
CitationJournal: Elife / Year: 2018
Title: The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells.
Authors: Fanning, S.W. / Jeselsohn, R. / Dharmarajan, V. / Mayne, C.G. / Karimi, M. / Buchwalter, G. / Houtman, R. / Toy, W. / Fowler, C.E. / Han, R. / Laine, M. / Carlson, K.E. / Martin, T.A. / ...Authors: Fanning, S.W. / Jeselsohn, R. / Dharmarajan, V. / Mayne, C.G. / Karimi, M. / Buchwalter, G. / Houtman, R. / Toy, W. / Fowler, C.E. / Han, R. / Laine, M. / Carlson, K.E. / Martin, T.A. / Nowak, J. / Nwachukwu, J.C. / Hosfield, D.J. / Chandarlapaty, S. / Tajkhorshid, E. / Nettles, K.W. / Griffin, P.R. / Shen, Y. / Katzenellenbogen, J.A. / Brown, M. / Greene, G.L.
History
DepositionJan 6, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2019Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Derived calculations / Structure summary
Category: pdbx_audit_support / pdbx_struct_oper_list / struct_keywords
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.pdbx_keywords
Revision 1.2Nov 27, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Mar 6, 2024Group: Advisory / Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_validate_close_contact / struct_conn
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)112,9618
Polymers111,0794
Non-polymers1,8824
Water70339
1
A: Estrogen receptor
C: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,4804
Polymers55,5392
Non-polymers9412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2780 Å2
ΔGint-10 kcal/mol
Surface area19210 Å2
MethodPISA
2
B: Estrogen receptor
D: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,4804
Polymers55,5392
Non-polymers9412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2640 Å2
ΔGint-7 kcal/mol
Surface area18600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.575, 59.165, 94.144
Angle α, β, γ (deg.)86.76, 75.36, 63.03
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 27769.641 Da / Num. of mol.: 4 / Fragment: UNP residues 306-548, Ligand Binding Domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P03372
#2: Chemical
ChemComp-29S / Bazedoxifene / 1-{4-[2-(azepan-1-yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol


Mass: 470.603 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H34N2O3 / Comment: medication*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.32 Å3/Da / Density % sol: 47.04 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.6 / Details: 33% PEG 3,350, 100 mM Tris pH 6.6, 250 mM MgCl2

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.987 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: May 26, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.49→50 Å / Num. obs: 33882 / % possible obs: 97.6 % / Redundancy: 2.2 % / Net I/σ(I): 2
Reflection shellResolution: 2.49→2.55 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.453 / Mean I/σ(I) obs: 0.05 / % possible all: 98

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-3000data reduction
HKL-3000data scaling
HKL-3000phasing
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QXS

2qxs


Resolution: 2.491→46.197 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 30.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2683 1704 5.03 %RANDOM
Rwork0.2151 ---
obs0.2178 33882 97.38 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.491→46.197 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6985 0 140 39 7164
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077323
X-RAY DIFFRACTIONf_angle_d1.7239945
X-RAY DIFFRACTIONf_dihedral_angle_d13.5912627
X-RAY DIFFRACTIONf_chiral_restr0.0441180
X-RAY DIFFRACTIONf_plane_restr0.0061226
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4914-2.56470.34841300.29792477X-RAY DIFFRACTION89
2.5647-2.64750.31081320.2732655X-RAY DIFFRACTION97
2.6475-2.74210.32441440.25912708X-RAY DIFFRACTION98
2.7421-2.85190.33221340.25652741X-RAY DIFFRACTION98
2.8519-2.98170.33741630.24372712X-RAY DIFFRACTION98
2.9817-3.13880.27571300.2382716X-RAY DIFFRACTION99
3.1388-3.33540.27161590.22932681X-RAY DIFFRACTION99
3.3354-3.59290.27041430.21892699X-RAY DIFFRACTION98
3.5929-3.95430.21221400.19562702X-RAY DIFFRACTION98
3.9543-4.5260.23121450.17952695X-RAY DIFFRACTION98
4.526-5.70060.27261340.20642709X-RAY DIFFRACTION98
5.7006-46.20540.26451500.20452683X-RAY DIFFRACTION98

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