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

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Basic information

Entry
Database: PDB / ID: 6wok
TitleCrystal structure of estrogen receptor alpha in complex with receptor degrader 6
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 / 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 / : / 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 / 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-G9J / Chem-U6D / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.309 Å
AuthorsKiefer, J.R. / Vinogradova, M. / Liang, J. / Zhang, B. / Wang, X. / Labadie, S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer.
Authors: Liang, J. / Blake, R. / Chang, J. / Friedman, L.S. / Goodacre, S. / Hartman, S. / Ingalla, E.R. / Kiefer, J.R. / Kleinheinz, T. / Labadie, S. / Li, J. / Lai, K.W. / Liao, J. / Mody, V. / ...Authors: Liang, J. / Blake, R. / Chang, J. / Friedman, L.S. / Goodacre, S. / Hartman, S. / Ingalla, E.R. / Kiefer, J.R. / Kleinheinz, T. / Labadie, S. / Li, J. / Lai, K.W. / Liao, J. / Mody, V. / McLean, N. / Metcalfe, C. / Nannini, M. / Otwine, D. / Ran, Y. / Ray, N. / Roussel, F. / Sambrone, A. / Sampath, D. / Vinogradova, M. / Wai, J. / Wang, T. / Yeap, K. / Young, A. / Zbieg, J. / Zhang, B. / Zheng, X. / Zhong, Y. / Wang, X.
History
DepositionApr 24, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2023Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_mutation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
D: Estrogen receptor
A: Estrogen receptor
C: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,80110
Polymers127,9214
Non-polymers2,8806
Water2,414134
1
D: Estrogen receptor
A: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,3775
Polymers63,9612
Non-polymers1,4163
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2900 Å2
ΔGint-13 kcal/mol
Surface area19050 Å2
MethodPISA
2
C: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,4245
Polymers63,9612
Non-polymers1,4633
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2880 Å2
ΔGint-15 kcal/mol
Surface area19330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.609, 59.102, 94.718
Angle α, β, γ (deg.)86.610, 74.780, 63.290
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 / Mutation: L372S,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-G9J / (2S)-3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-1-benzopyran-6-ol


Mass: 456.273 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H17IO3
#3: Chemical ChemComp-U6D / (1R,3R)-1-(2,6-difluoro-4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline


Mass: 503.575 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C28H33F4N3O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 134 / 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: 2.02 Å3/Da / Density % sol: 39.03 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: 25-35% PEG 3,350 0.1 M Bis-Tris (pH 6.1-6.5) 150-300 mM MgCl2
PH range: 6.1 - 6.5

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 29, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→40 Å / Num. obs: 32320 / % possible obs: 73.7 % / Redundancy: 1.6 % / Rmerge(I) obs: 0.046 / Rpim(I) all: 0.046 / Rrim(I) all: 0.065 / Χ2: 0.976 / Net I/σ(I): 8.8 / Num. measured all: 50113
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.3-2.341.40.3114530.5740.310.4390.61965.2
2.34-2.381.40.29214640.670.2920.4120.59666.8
2.38-2.431.40.27114810.7080.2710.3830.6366.8
2.43-2.481.40.23114670.7810.2310.3260.64868.4
2.48-2.531.40.22214970.7890.2220.3140.68667.2
2.53-2.591.40.1914960.8320.190.2690.67869.5
2.59-2.661.40.14415050.9220.1440.2040.59667.8
2.66-2.731.40.14715280.8980.1470.2070.68670.3
2.73-2.811.50.13914920.9260.1390.1960.79266.4
2.81-2.91.50.10112320.9560.1010.1430.77158
2.9-31.50.0916620.9660.090.1270.90275.3
3-3.121.50.08317120.9660.0830.1180.90577.6
3.12-3.261.60.06517500.9840.0650.0910.87880.3
3.26-3.441.60.05617540.9860.0560.0791.10381
3.44-3.651.70.04518250.9890.0450.0641.09682.6
3.65-3.931.70.0417680.9910.040.0571.06980.3
3.93-4.331.70.03415710.9920.0340.0481.1172.5
4.33-4.951.80.03219280.9950.0320.0451.07887.6
4.95-6.241.70.03618830.9930.0360.051.12386.8
6.24-401.80.03918520.9940.0390.0551.7184.1

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
SCALEPACKdata scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NA

Resolution: 2.309→38.449 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 2.03 / Phase error: 27.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2503 1214 3.76 %
Rwork0.1724 31092 -
obs0.1753 32306 73.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 244.11 Å2 / Biso mean: 51.4118 Å2 / Biso min: 24.42 Å2
Refinement stepCycle: final / Resolution: 2.309→38.449 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7166 0 186 135 7487
Biso mean--51.83 43.64 -
Num. residues----919
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087516
X-RAY DIFFRACTIONf_angle_d1.08410204
X-RAY DIFFRACTIONf_dihedral_angle_d3.9316164
X-RAY DIFFRACTIONf_chiral_restr0.0521200
X-RAY DIFFRACTIONf_plane_restr0.0061249
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.309-2.40120.3461170.239306665
2.4012-2.51050.29191260.2132315167
2.5105-2.64280.31881130.2095322669
2.6428-2.80840.31191300.2093322568
2.8084-3.02510.29111400.1942310767
3.0251-3.32940.29741390.1841374679
3.3294-3.81080.23661560.1643384882
3.8108-4.79980.21281350.1413371779
4.7998-38.4490.21361580.1621400685
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)
11.4687-1.01380.02683.0086-0.65022.14170.0927-0.04930.0964-0.2164-0.1075-0.0591-0.12660.0275-0.00020.2993-0.0609-0.01470.3302-0.03190.368830.1432-2.67439.1305
22.21950.26440.73722.37820.37853.1203-0.1124-0.04110.118-0.0004-0.07730.3170.1117-0.31030.00030.3138-0.04510.00850.3106-0.00750.360518.5242-25.385939.7114
31.5980.42990.01683.0605-0.5851.80810.09630.0293-0.15440.1329-0.1105-0.04820.15930.024800.35430.06850.01470.3671-0.01480.376629.7737-9.1062-6.1725
42.2633-0.3873-0.30912.21890.65682.7625-0.0074-0.0532-0.04480.163-0.12250.1367-0.1591-0.1867-0.00010.33970.0063-0.0020.30540.02560.307918.160313.6384-6.9975
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'D' and resid 306 through 545)D306 - 545
2X-RAY DIFFRACTION2(chain 'A' and resid 306 through 545)A306 - 545
3X-RAY DIFFRACTION3(chain 'C' and resid 306 through 545)C306 - 545
4X-RAY DIFFRACTION4(chain 'B' and resid 306 through 545)B306 - 545

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