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

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Basic information

Entry
Database: PDB / ID: 6dfn
TitleCrystal structure of estrogen receptor alpha in complex with receptor degrader 16aa
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 / 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-G91 / Chem-G9J / NICKEL (II) ION / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 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 15, 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)131,06014
Polymers127,9214
Non-polymers3,13910
Water81145
1
A: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,6068
Polymers63,9612
Non-polymers1,6456
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3480 Å2
ΔGint-20 kcal/mol
Surface area19200 Å2
MethodPISA
2
C: Estrogen receptor
D: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,4556
Polymers63,9612
Non-polymers1,4944
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-12 kcal/mol
Surface area18600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.089, 59.134, 94.180
Angle α, β, γ (deg.)86.05, 74.92, 63.34
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Beg auth comp-ID: LEU / Beg label comp-ID: LEU / End auth comp-ID: ALA / End label comp-ID: ALA / Refine code: 0

Dom-IDEns-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11AA306 - 54633 - 273
21BB306 - 54633 - 273
12AA308 - 54635 - 273
22CC308 - 54635 - 273
13AA306 - 54633 - 273
23DD306 - 54633 - 273
14BB308 - 54635 - 273
24CC308 - 54635 - 273
15BB306 - 54633 - 273
25DD306 - 54633 - 273
16CC308 - 54635 - 273
26DD308 - 54635 - 273

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Protein , 1 types, 4 molecules ABCD

#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

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Non-polymers , 5 types, 55 molecules

#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.: 4 / Source method: obtained synthetically / Formula: C22H17IO3
#3: Chemical ChemComp-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#4: Chemical ChemComp-G91 / (8S)-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.: 2 / Source method: obtained synthetically / Formula: C29H28FNO5
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 38.23 %
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: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.839
11H, H-K, H-L20.161
ReflectionResolution: 2.11→30 Å / Num. obs: 51361 / % possible obs: 94.9 % / Redundancy: 2 % / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.045 / Rrim(I) all: 0.067 / Χ2: 1.037 / Net I/σ(I): 9.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.15-2.191.80.62324830.5290.5760.8510.48190.9
2.19-2.231.80.61824480.4960.5630.8390.48490.7
2.23-2.271.90.51425170.6210.4640.6940.54692.9
2.27-2.321.90.49525220.7070.4490.670.52493.6
2.32-2.371.90.40825670.8010.3670.550.55495
2.37-2.421.90.35425630.8030.320.4790.53494.9
2.42-2.4820.26525910.8960.2390.3580.60695.4
2.48-2.5520.23125760.910.2070.3110.64395.1
2.55-2.6220.1925560.940.1720.2570.67295.3
2.62-2.7120.16325990.9550.1470.220.79495.5
2.71-2.8120.12826270.9740.1150.1720.79596.1
2.81-2.922.10.10726010.9790.0960.1440.89397.1
2.92-3.052.10.08226070.9870.0740.111.03697
3.05-3.212.10.06726180.9920.060.091.08297.4
3.21-3.412.10.05326800.9940.0480.0721.3497.6
3.41-3.672.10.04226060.9960.0390.0581.54496.6
3.67-4.042.10.03825830.9960.0350.0511.89196.3
4.04-4.632.10.03325630.9960.030.0441.94794.5
4.63-5.822.10.03125600.9960.0280.0421.71194.6
5.82-302.10.02924940.9970.0260.041.78692

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
SCALEPACKdata scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in house model

Resolution: 2.1→29.47 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.93 / SU B: 10.035 / SU ML: 0.133 / Cross valid method: THROUGHOUT / ESU R: 0.07 / ESU R Free: 0.048 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26503 2598 5.1 %RANDOM
Rwork0.2475 ---
obs0.24837 48761 89.24 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 62.522 Å2
Baniso -1Baniso -2Baniso -3
1-40.14 Å2-3.73 Å27.61 Å2
2---58.16 Å211.19 Å2
3---18.02 Å2
Refinement stepCycle: 1 / Resolution: 2.1→29.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6963 0 195 45 7203
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0197340
X-RAY DIFFRACTIONr_bond_other_d0.0020.027100
X-RAY DIFFRACTIONr_angle_refined_deg1.1581.9969941
X-RAY DIFFRACTIONr_angle_other_deg0.906316260
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8365894
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.36424.281278
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.893151298
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6871533
X-RAY DIFFRACTIONr_chiral_restr0.0690.21171
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.028277
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021568
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0294.1133612
X-RAY DIFFRACTIONr_mcbond_other1.0294.1123611
X-RAY DIFFRACTIONr_mcangle_it1.686.1544494
X-RAY DIFFRACTIONr_mcangle_other1.686.1554495
X-RAY DIFFRACTIONr_scbond_it1.0614.2553728
X-RAY DIFFRACTIONr_scbond_other1.064.2553728
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.6776.3425444
X-RAY DIFFRACTIONr_long_range_B_refined3.85448.8018045
X-RAY DIFFRACTIONr_long_range_B_other3.85448.8088046
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A131720.08
12B131720.08
21A142140.06
22C142140.06
31A133840.09
32D133840.09
41B131960.07
42C131960.07
51B131820.07
52D131820.07
61C130480.09
62D130480.09
LS refinement shellResolution: 2.101→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 43 -
Rwork0.297 672 -
obs--16.94 %
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)
11.8626-0.0910.36843.7398-0.74132.541-0.04430.09470.12840.01250.0118-0.0573-0.12830.0880.03250.0183-0.0384-0.00730.2486-0.06350.0567-51.8395.582-49.5394
23.10090.6980.51983.3632-0.11782.9785-0.01390.00720.04360.04560.03620.32540.2079-0.1938-0.02230.0369-0.00270.01590.2011-0.04120.0532-62.9095-17.596-48.9882
31.70210.4517-0.21824.2434-0.70222.59220.0022-0.0358-0.113-0.063-0.0193-0.22790.16940.11110.01710.05990.10420.01090.2568-0.04670.101-51.8176-1.2956-94.3371
42.704-0.0393-0.27183.4471-0.35543.5102-0.0061-0.0325-0.0301-0.0783-0.00480.1212-0.052-0.15830.01090.02950.0726-0.01280.1901-0.02660.0086-62.978321.5337-94.8745
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A306 - 546
2X-RAY DIFFRACTION2B306 - 546
3X-RAY DIFFRACTION3C308 - 546
4X-RAY DIFFRACTION4D306 - 546

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