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- PDB-5tlf: Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) i... -

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Basic information

Entry
Database: PDB / ID: 5tlf
TitleCrystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with the Constrained WAY Derivative, 4-(2-(3-methylbut-2-en-1-yl)-7-(trifluoromethyl)-2H-indazol-3-yl)benzene-1,3-diol
Components
  • Estrogen receptor
  • NUCLEAR RECEPTOR COACTIVATOR 2
KeywordsTRANSCRIPTION / Nuclear receptor / transcription factor / ligand binding / protein-ligand complex
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 / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / 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 ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / 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 / locomotor rhythm / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / vagina development / aryl hydrocarbon receptor binding / TFIIB-class transcription factor binding / androgen metabolic process / regulation of lipid metabolic process / steroid hormone receptor signaling pathway / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / mammary gland alveolus development / cellular response to estrogen stimulus / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / estrogen response element binding / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / 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 / Recycling of bile acids and salts / cellular response to hormone stimulus / 14-3-3 protein binding / protein localization to chromatin / estrogen receptor signaling pathway / positive regulation of adipose tissue development / RORA activates gene expression / peroxisome proliferator activated receptor signaling pathway / steroid binding / nitric-oxide synthase regulator activity / Regulation of lipid metabolism by PPARalpha / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / regulation of cellular response to insulin stimulus / ESR-mediated signaling / BMAL1:CLOCK,NPAS2 activates circadian gene expression / transcription corepressor binding / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / nuclear receptor coactivator activity / positive regulation of nitric-oxide synthase activity / cellular response to estradiol stimulus / transcription coregulator binding / response to progesterone / nuclear receptor binding / stem cell differentiation / nuclear estrogen receptor binding / positive regulation of DNA-binding transcription factor activity / circadian regulation of gene expression / SUMOylation of intracellular receptors / Heme signaling / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / euchromatin / negative regulation of DNA-binding transcription factor activity / PPARA activates gene expression / Cytoprotection by HMOX1 / transcription coactivator binding / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / beta-catenin binding / response to estrogen / RNA polymerase II transcription regulator complex / 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 / Circadian Clock / PIP3 activates AKT signaling / response to estradiol / HATs acetylate histones / 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
Similarity search - Function
Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 receptor coactivator, DUF1518 ...Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / 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 receptor coactivator, DUF1518 / Nuclear receptor coactivator, Ncoa-type, interlocking / Nuclear receptor coactivator, Ncoa-type, interlocking domain superfamily / Nuclear receptor coactivator, DUF1518 / Nuclear receptor coactivator / DUF1518 / Nuclear receptor coactivator, receptor-binding domain / Nuclear receptor coactivator / Steroid receptor coactivator / Unstructured region on nuclear receptor coactivator protein / PAS domain / : / Nuclear receptor coactivator, interlocking / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / Retinoid X Receptor / Retinoid X Receptor / PAS domain superfamily / 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-7EF / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.204 Å
AuthorsNwachukwu, J.C. / Srinivasan, S. / Bruno, N.E. / Nowak, J. / Kojetin, D.J. / Elemento, O. / Katzenellenbogen, J.A. / Nettles, K.W.
CitationJournal: Cell Chem Biol / Year: 2017
Title: Systems Structural Biology Analysis of Ligand Effects on ER alpha Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies.
Authors: Nwachukwu, J.C. / Srinivasan, S. / Bruno, N.E. / Nowak, J. / Wright, N.J. / Minutolo, F. / Rangarajan, E.S. / Izard, T. / Yao, X.Q. / Grant, B.J. / Kojetin, D.J. / Elemento, O. / ...Authors: Nwachukwu, J.C. / Srinivasan, S. / Bruno, N.E. / Nowak, J. / Wright, N.J. / Minutolo, F. / Rangarajan, E.S. / Izard, T. / Yao, X.Q. / Grant, B.J. / Kojetin, D.J. / Elemento, O. / Katzenellenbogen, J.A. / Nettles, K.W.
History
DepositionOct 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2017Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Mar 6, 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

Downloads & links

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Assembly

Deposited unit
A: Estrogen receptor
B: Estrogen receptor
C: NUCLEAR RECEPTOR COACTIVATOR 2
D: NUCLEAR RECEPTOR COACTIVATOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,4836
Polymers61,7594
Non-polymers7252
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5240 Å2
ΔGint-31 kcal/mol
Surface area20370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.655, 81.567, 58.651
Angle α, β, γ (deg.)90.000, 109.960, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 29299.535 Da / Num. of mol.: 2 / Fragment: ligand-binding domain / Mutation: 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) / Strain (production host): BL21(DE3) / References: UniProt: P03372
#2: Protein/peptide NUCLEAR RECEPTOR COACTIVATOR 2


Mass: 1579.866 Da / Num. of mol.: 2 / Fragment: Nuclear receptor-interacting peptide / Source method: obtained synthetically / Details: This sequence occurs naturally in humans / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596*PLUS
#3: Chemical ChemComp-7EF / 4-[2-(3-methylbut-2-en-1-yl)-7-(trifluoromethyl)-2H-indazol-3-yl]benzene-1,3-diol


Mass: 362.346 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H17F3N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 161 / 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: 38.18 % / Mosaicity: 0.874 °
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 8.3 / Details: 15% PEG 3350, 0.05M MgCl2, 0.067M NaCl, 0.1M Tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 24, 2014
RadiationMonochromator: Side scattering bent cube i-beam single crystal asymmetric cut 4.965 degs
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.204→50 Å / Num. obs: 23906 / % possible obs: 97.9 % / Redundancy: 3.4 % / Biso Wilson estimate: 35.92 Å2 / Rmerge(I) obs: 0.096 / Net I/av σ(I): 17.943 / Net I/σ(I): 6.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Diffraction-ID% possible all
2.21-2.253.40.4590.855198.8
2.25-2.293.40.4290.826198.4
2.29-2.333.40.3570.844198.6
2.33-2.383.50.3080.899198.9
2.38-2.433.40.2750.912198.6
2.43-2.493.50.2390.926198.6
2.49-2.553.40.2320.929198.4
2.55-2.623.40.20.947198.4
2.62-2.73.40.1780.954196.6
2.7-2.783.20.1550.96195.6
2.78-2.883.20.1330.975195.6
2.88-33.60.1190.974198.9
3-3.143.50.1050.983198.9
3.14-3.33.50.0990.981198.8
3.3-3.513.40.0850.986198.9
3.51-3.783.40.0790.987198.6
3.78-4.163.10.0740.987194.4
4.16-4.763.50.0770.989199
4.76-63.40.0830.986198.9
6-503.10.0770.989195.8

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.2data extraction
HKL-2000data scaling
HKL-2000data reduction
PHENIXphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.204→46.28 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 24.37
RfactorNum. reflection% reflection
Rfree0.2291 1932 8.46 %
Rwork0.1878 --
obs0.1912 22831 93.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 154.36 Å2 / Biso mean: 47.7181 Å2 / Biso min: 14.35 Å2
Refinement stepCycle: final / Resolution: 2.204→46.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3849 0 52 161 4062
Biso mean--42.46 43.25 -
Num. residues----492
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053972
X-RAY DIFFRACTIONf_angle_d0.9215380
X-RAY DIFFRACTIONf_chiral_restr0.039635
X-RAY DIFFRACTIONf_plane_restr0.004665
X-RAY DIFFRACTIONf_dihedral_angle_d16.0791443
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2044-2.25950.31091280.27011289141781
2.2595-2.32060.25291340.22981354148886
2.3206-2.38890.28051280.22591467159592
2.3889-2.4660.28821530.21181463161692
2.466-2.55410.28321330.20681488162193
2.5541-2.65640.26591410.2161473161493
2.6564-2.77730.25561200.21161462158291
2.7773-2.92370.281470.2031488163593
2.9237-3.10680.23861360.19881557169397
3.1068-3.34660.26961390.20621571171098
3.3466-3.68330.23451430.1811581172498
3.6833-4.2160.1891370.16021518165595
4.216-5.31040.17561500.15781593174399
5.3104-46.290.20981430.17841595173896
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)
10.22870.3360.2714.46731.67211.03640.43530.32390.8773-0.4147-0.56460.1862-0.5696-0.43680.02830.55030.11670.00190.48070.05810.50331.948119.8245-4.4101
21.29560.7391-0.24510.6610.0372.27530.58080.8363-0.4556-1.2581-0.9471-0.43510.8170.3437-0.03770.55820.08850.07590.59040.02320.449920.7086-6.4113-6.3833
33.0599-0.1902-0.04772.40391.00191.8557-0.0460.12820.22160.06620.0295-0.1617-0.03770.24510.03430.26240.0045-0.00620.28930.02860.279517.63768.09262.3314
43.0966-0.1082-2.25033.01210.77483.761-0.29940.0857-0.7570.1574-0.04410.02850.60420.17140.25450.4773-0.01180.03350.2734-0.00180.374811.5872-9.89863.5655
55.7156-0.11760.17672.92750.18072.68640.0612-0.00960.30520.0916-0.13450.0965-0.0454-0.07560.05680.28660.00310.02590.2154-0.01230.19583.9458.28627.7222
66.98030.3914-0.29464.8637-0.52044.7898-0.1771-0.4933-0.38480.28340.2246-0.54390.94660.9573-0.00770.45050.0578-0.00110.56370.04860.569728.8964.48478.9248
75.19820.70142.47682.10540.15234.81660.0199-0.2105-0.30350.22690.13020.03250.0703-0.11990.00110.3540.08790.07090.4625-0.06120.4048-2.59516.293536.1748
82.065-0.8344-0.06093.09081.23234.61-0.134-0.2741-0.1090.13990.05520.12570.15420.10170.01460.3410.00730.03080.3490.03710.25374.00693.200632.9853
94.42680.28830.14923.87561.13364.46680.0408-0.2630.2917-0.14020.0453-0.268-0.72130.14420.07480.4033-0.05580.02170.2733-0.04010.2124.379912.661325.7926
101.90813.67081.12227.2412.0580.61830.22110.4369-0.552-0.52920.0471-0.17610.85520.3801-0.26530.97270.08290.0530.74250.07690.65081.6409-10.157215.7634
113.0814-0.6879-0.49440.1873-0.00133.93130.0387-0.0631-0.4628-0.2732-0.10941.08190.4833-0.75140.07870.3323-0.06810.01060.4848-0.04840.3689-10.89282.787816.4297
123.5725-0.71350.78192.986-1.06174.0976-0.1244-0.0834-0.16860.2928-0.1178-0.35870.06140.48230.16830.31210.02680.02980.2691-0.04010.3358.84183.811724.0053
130.61190.0198-0.30671.9847-1.72641.61090.1321-0.07390.8570.1574-0.47090.0636-0.67580.756-0.07380.3681-0.0780.00550.51130.00870.582626.47818.04891.6714
140.2498-0.13020.58131.20920.67312.1869-0.4068-0.7245-1.39040.52450.0989-0.07590.9979-0.2694-1.40750.6531-0.0290.08530.56370.1970.62321.0329-13.446136.0373
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 304 through 321 )A304 - 321
2X-RAY DIFFRACTION2chain 'A' and (resid 322 through 338 )A322 - 338
3X-RAY DIFFRACTION3chain 'A' and (resid 339 through 394 )A339 - 394
4X-RAY DIFFRACTION4chain 'A' and (resid 395 through 437 )A395 - 437
5X-RAY DIFFRACTION5chain 'A' and (resid 438 through 530 )A438 - 530
6X-RAY DIFFRACTION6chain 'A' and (resid 531 through 548 )A531 - 548
7X-RAY DIFFRACTION7chain 'B' and (resid 305 through 338 )B305 - 338
8X-RAY DIFFRACTION8chain 'B' and (resid 339 through 411 )B339 - 411
9X-RAY DIFFRACTION9chain 'B' and (resid 412 through 455 )B412 - 455
10X-RAY DIFFRACTION10chain 'B' and (resid 456 through 468 )B456 - 468
11X-RAY DIFFRACTION11chain 'B' and (resid 469 through 496 )B469 - 496
12X-RAY DIFFRACTION12chain 'B' and (resid 497 through 548 )B497 - 548
13X-RAY DIFFRACTION13chain 'C' and (resid 687 through 696 )C687 - 696
14X-RAY DIFFRACTION14chain 'D' and (resid 688 through 697 )D688 - 697

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