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- PDB-7wnv: Crystal structure of mutant estrogen receptor alpha Y537S in comp... -

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Basic information

Entry
Database: PDB / ID: 7wnv
TitleCrystal structure of mutant estrogen receptor alpha Y537S in complex with CO9
ComponentsEstrogen receptor
KeywordsNUCLEAR PROTEIN / Covalent Inhibitor Transcription factor Oncogene
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 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / steroid binding / nitric-oxide synthase regulator activity / ESR-mediated signaling / 14-3-3 protein binding / 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 / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / positive regulation of DNA-binding transcription factor activity / response to estrogen / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of RUNX2 expression and activity / 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-2I9 / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsXiao, Y. / Lv, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Chem. / Year: 2023
Title: X-ray crystallography study and optimization of novel benzothiophene analogs as potent selective estrogen receptor covalent antagonists (SERCAs) with improved potency and safety profiles.
Authors: Bai, C. / Lv, Y. / Xiong, S. / Wu, S. / Qi, L. / Ren, S. / Zhu, M. / Dong, H. / Shen, H. / Li, Z. / Zhu, Y. / Ye, H. / Hao, H. / Xiao, Y. / Xiang, H. / Luo, G.
History
DepositionJan 19, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 25, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Feb 7, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)120,0258
Polymers118,0074
Non-polymers2,0184
Water1,53185
1
A: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,0134
Polymers59,0032
Non-polymers1,0092
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2460 Å2
ΔGint-6 kcal/mol
Surface area19430 Å2
MethodPISA
2
C: Estrogen receptor
D: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,0134
Polymers59,0032
Non-polymers1,0092
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2470 Å2
ΔGint-5 kcal/mol
Surface area19570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.928, 58.834, 93.062
Angle α, β, γ (deg.)90.310, 105.390, 117.150
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: 29501.738 Da / Num. of mol.: 4 / Mutation: C417S Y537S
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-2I9 / (~{Z})-4-[2-[4-[[2-(4-hydroxyphenyl)-6-oxidanyl-1-benzothiophen-3-yl]oxy]phenoxy]ethylamino]-~{N},~{N}-dimethyl-but-2-enamide


Mass: 504.597 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H28N2O5S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 85 / 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: 2.13 Å3/Da / Density % sol: 42.24 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop
Details: PEG 3350, sodium citrate tribasic dihydrate, magnesium chloride
PH range: 5.0 - 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.3→19.67 Å / Num. obs: 41425 / % possible obs: 96.01 % / Redundancy: 3.59 % / Rmerge(I) obs: 0.06556 / Rpim(I) all: 0.03951 / Rrim(I) all: 0.07667 / Net I/σ(I): 13.56
Reflection shellResolution: 2.3→2.382 Å / Num. unique obs: 41425 / CC1/2: 0.998 / CC star: 0.999

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.19.2_4158phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6OWC

6owc


Resolution: 2.3→19.67 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 26.23 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2355 1687 4.07 %
Rwork0.203 39720 -
obs0.2043 41407 96.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 98.21 Å2 / Biso mean: 42.455 Å2 / Biso min: 19.81 Å2
Refinement stepCycle: final / Resolution: 2.3→19.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6919 0 144 85 7148
Biso mean--45.86 35.72 -
Num. residues----886
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.370.28821450.25483317346297
2.37-2.440.30291470.2333363351097
2.44-2.530.29671380.22943289342796
2.53-2.630.27641440.2273333347797
2.63-2.750.31781280.22983320344896
2.75-2.90.28991460.23623268341495
2.9-3.080.28151430.22093344348797
3.08-3.310.27541350.22253367350297
3.31-3.650.22551440.20043243338795
3.65-4.170.1941340.17383343347796
4.17-5.230.18051410.17723282342396
5.24-19.670.20521420.18863251339394
Refinement TLS params.Method: refined / Origin x: 13.5829 Å / Origin y: -5.3054 Å / Origin z: -21.9904 Å
111213212223313233
T0.2051 Å20.0088 Å2-0.0291 Å2-0.2026 Å20.0085 Å2--0.2398 Å2
L0.234 °2-0.0711 °2-0.238 °2-0.2307 °20.0342 °2--0.5912 °2
S-0.0259 Å °-0.0066 Å °0.0134 Å °-0.0021 Å °0.0195 Å °0.0384 Å °-0.0389 Å °-0.0006 Å °0.0152 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA307 - 546
2X-RAY DIFFRACTION1allB305 - 544
3X-RAY DIFFRACTION1allC307 - 545
4X-RAY DIFFRACTION1allD307 - 544
5X-RAY DIFFRACTION1allE1 - 4
6X-RAY DIFFRACTION1allS3 - 252

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