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- PDB-6df6: Crystal structure of estrogen receptor alpha in complex with rece... -

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Basic information

Entry
Database: PDB / ID: 6df6
TitleCrystal structure of estrogen receptor alpha in complex with receptor degrader 16ab
ComponentsEstrogen receptor
KeywordsNUCLEAR PROTEIN / ERA / antagonist / inverse agonist / receptor / breast cancer / degrader / ligand / estrogen 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 / prostate epithelial cord elongation / epithelial cell development / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / TFIIB-class transcription factor binding / androgen metabolic process / steroid hormone mediated signaling pathway / mammary gland alveolus development / intracellular estrogen receptor signaling pathway / cellular response to estrogen stimulus / estrogen response element binding / Nuclear signaling by ERBB4 / positive regulation of phospholipase C activity / intracellular steroid hormone receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / 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 / positive regulation of nitric-oxide synthase activity / cellular response to estradiol stimulus / nuclear estrogen receptor binding / transcription coregulator binding / stem cell differentiation / euchromatin / SUMOylation of intracellular receptors / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / male gonad development / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / positive regulation of nitric oxide biosynthetic process / positive regulation of DNA-binding transcription factor activity / 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 / fibroblast proliferation / regulation of inflammatory response / 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 / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. ...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
Chem-G8Y / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsKiefer, J.R. / Vinogradova, M. / Liang, J. / Zhang, B. / Ortwine, D.F. / Nettles, K.W. / Nwachukwu, J.C.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2019
Title: Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha.
Authors: Zhang, B. / Kiefer, J.R. / Blake, R.A. / Chang, J.H. / Hartman, S. / Ingalla, E.R. / Kleinheinz, T. / Mody, V. / Nannini, M. / Ortwine, D.F. / Ran, Y. / Sambrone, A. / Sampath, D. / ...Authors: Zhang, B. / Kiefer, J.R. / Blake, R.A. / Chang, J.H. / Hartman, S. / Ingalla, E.R. / Kleinheinz, T. / Mody, V. / Nannini, M. / Ortwine, D.F. / Ran, Y. / Sambrone, A. / Sampath, D. / Vinogradova, M. / Zhong, Y. / Nwachukwu, J.C. / Nettles, K.W. / Lai, T. / Liao, J. / Zheng, X. / Chen, H. / Wang, X. / Liang, J.
History
DepositionMay 14, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 20, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)130,06410
Polymers127,9214
Non-polymers2,1426
Water36020
1
A: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0325
Polymers63,9612
Non-polymers1,0713
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3070 Å2
ΔGint-7 kcal/mol
Surface area19180 Å2
MethodPISA
2
C: Estrogen receptor
D: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0325
Polymers63,9612
Non-polymers1,0713
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3310 Å2
ΔGint-9 kcal/mol
Surface area19430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.386, 58.857, 94.046
Angle α, β, γ (deg.)79.750, 75.420, 63.100
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: 31980.295 Da / Num. of mol.: 4
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-G8Y / (8R)-8-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-1,8-dihydro-2H-[1]benzopyrano[4,3-d][1]benzoxepine-5,11-diol


Mass: 489.535 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C29H28FNO5
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 20 / Source method: isolated from a natural source / Formula: H2O

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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: 1.99 Å3/Da / Density % sol: 38.14 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: grid of PEG 3350 vs. MgCl2 with a buffer of Bis-TRIS at pH 6-6.5

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.00004 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 2.5→35 Å / Num. obs: 27230 / % possible obs: 81.1 % / Redundancy: 1.7 % / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.077 / Rrim(I) all: 0.108 / Χ2: 1.009 / Net I/σ(I): 6.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.5-2.591.20.4648100.5220.4640.6560.38624.2
2.59-2.691.30.44416430.6620.4440.6270.53348.7
2.69-2.821.50.4125080.70.410.580.54474.1
2.82-2.961.60.31730850.790.3170.4480.5891.9
2.96-3.151.80.25531730.8360.2550.360.74995.5
3.15-3.391.80.16631970.9330.1660.2350.86795.1
3.39-3.731.80.11431810.9610.1140.1621.19595
3.73-4.271.80.07532080.9810.0750.1061.44595.5
4.27-5.381.80.05732230.9880.0570.081.33195.6
5.38-301.80.03932020.9950.0390.0551.09795.6

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Processing

Software
NameVersionClassification
HKL-2000data reduction
SCALEPACKdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.24data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→35 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.899 / SU B: 18.322 / SU ML: 0.365 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.399
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2727 1385 5.1 %RANDOM
Rwork0.2183 ---
obs0.221 25828 79.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 115.41 Å2 / Biso mean: 54.465 Å2 / Biso min: 17.36 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20.86 Å20.13 Å2
2---2.23 Å20.64 Å2
3---3.75 Å2
Refinement stepCycle: final / Resolution: 2.5→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7145 0 156 20 7321
Biso mean--58.84 42.17 -
Num. residues----919
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0197481
X-RAY DIFFRACTIONr_bond_other_d0.0010.027189
X-RAY DIFFRACTIONr_angle_refined_deg1.112210135
X-RAY DIFFRACTIONr_angle_other_deg0.86316482
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3685911
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.16724.247292
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.67151323
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1131534
X-RAY DIFFRACTIONr_chiral_restr0.0530.21191
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.028164
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021596
LS refinement shellResolution: 2.5→2.565 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 21 -
Rwork0.341 459 -
all-480 -
obs--18.71 %

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