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- PDB-4iw6: Crystal Structure of the Estrogen Receptor alpha Ligand-binding D... -

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Basic information

Entry
Database: PDB / ID: 4iw6
TitleCrystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with Constrained WAY-derivative, 7b
Components
  • Estrogen receptor
  • Nuclear receptor coactivator 2
KeywordsTRANSCRIPTION / Nuclear hormone receptor / Transcription factor / Ligand-binding / Nucleus
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / antral ovarian follicle growth / 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 / epithelial cell development / steroid hormone receptor signaling pathway ...regulation of epithelial cell apoptotic process / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / antral ovarian follicle growth / 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 / epithelial cell development / steroid hormone receptor signaling pathway / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / locomotor rhythm / mammary gland branching involved in pregnancy / uterus development / negative regulation of smooth muscle cell apoptotic process / aryl hydrocarbon receptor binding / vagina development / TFIIB-class transcription factor binding / cellular response to Thyroglobulin triiodothyronine / regulation of lipid metabolic process / androgen metabolic process / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Mitochondrial unfolded protein response (UPRmt) / nuclear receptor-mediated steroid hormone signaling pathway / negative regulation of DNA-binding transcription factor activity / positive regulation of DNA-binding transcription factor activity / Nuclear signaling by ERBB4 / cellular response to hormone stimulus / Recycling of bile acids and salts / RNA polymerase II preinitiation complex assembly / transcription regulator inhibitor activity / positive regulation of nitric-oxide synthase activity / estrogen receptor signaling pathway / protein localization to chromatin / : / positive regulation of adipose tissue development / steroid binding / 14-3-3 protein binding / Regulation of lipid metabolism by PPARalpha / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / negative regulation of canonical NF-kappaB signal transduction / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / response to progesterone / ESR-mediated signaling / negative regulation of miRNA transcription / TBP-class protein binding / nuclear estrogen receptor binding / nitric-oxide synthase regulator activity / nuclear receptor binding / transcription corepressor binding / transcription coregulator binding / negative regulation of smoothened signaling pathway / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / Heme signaling / euchromatin / Transcriptional activation of mitochondrial biogenesis / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / PPARA activates gene expression / Cytoprotection by HMOX1 / beta-catenin binding / Nuclear Receptor transcription pathway / Transcriptional regulation of white adipocyte differentiation / response to estrogen / RNA polymerase II transcription regulator complex / transcription coactivator binding / male gonad development / nuclear receptor activity / positive regulation of fibroblast proliferation / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of RUNX2 expression and activity / positive regulation of nitric oxide biosynthetic process / sequence-specific double-stranded DNA binding / Ovarian tumor domain proteases / : / response to estradiol / PIP3 activates AKT signaling / HATs acetylate histones / positive regulation of cytosolic calcium ion concentration / ATPase binding / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of inflammatory response / fibroblast proliferation
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 / Nuclear receptor coactivators bHLH domain / 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 / 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-1GU / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.98 Å
AuthorsNwachukwu, J.C. / Srinivasan, S. / Parent, A.A. / Cavett, V. / Nowak, J. / Hughes, T.S. / Kojetin, D.J. / Katzenellenbogen, J.A. / Nettles, K.W.
CitationJournal: Nat.Chem.Biol. / Year: 2013
Title: Ligand binding dynamics rewire cellular signaling via Estrogen Receptor-alpha
Authors: Srinivasan, S. / Nwachukwu, J.C. / Parent, A.A. / Cavett, V. / Nowak, J. / Hughes, T.S. / Kojetin, D.J. / Katzenellenbogen, J.A. / Nettles, K.W.
History
DepositionJan 23, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2013Group: Database references
Revision 1.2Feb 26, 2020Group: Database references / Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / struct_ref_seq_dif
Item: _struct_ref_seq_dif.details
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Estrogen receptor
C: Nuclear receptor coactivator 2
B: Estrogen receptor
D: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,6286
Polymers58,9324
Non-polymers6972
Water3,549197
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5280 Å2
ΔGint-29 kcal/mol
Surface area20430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.727, 81.627, 58.474
Angle α, β, γ (deg.)90.00, 109.77, 90.00
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: 28189.229 Da / Num. of mol.: 2 / Fragment: Ligand-binding Domain, UNP residues 303-549 / Mutation: Y537S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR, ESR1, NR3A1 / Production host: Escherichia coli (E. coli) / References: UniProt: P03372
#2: Protein/peptide Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1276.530 Da / Num. of mol.: 2
Fragment: Receptor-interacting peptide, UNP residues 687-696
Source method: obtained synthetically / Details: This sequence occurs naturally in humans / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-1GU / 4-[2-(but-3-en-1-yl)-7-(trifluoromethyl)-2H-indazol-3-yl]benzene-1,3-diol


Mass: 348.319 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15F3N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / 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: 2.09 Å3/Da / Density % sol: 41.02 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 8.3
Details: 15% PEG 3350, 0.05M magnesium chloride, 0.067M sodium chloride, 0.1M Tris, pH 8.3, VAPOR DIFFUSION, HANGING DROP, temperature 294K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 27, 2012
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: 1 Å / Relative weight: 1
ReflectionResolution: 1.98→50 Å / Num. all: 33288 / Num. obs: 33288 / % possible obs: 97.76 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 6.6 % / Biso Wilson estimate: 32.69 Å2 / Rsym value: 0.076 / Net I/σ(I): 16.55
Reflection shellResolution: 1.98→2.01 Å / Redundancy: 6.6 % / Mean I/σ(I) obs: 2.54 / Rsym value: 0.643 / % possible all: 93.74

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHENIX(phenix.automr)model building
PHENIX(phenix.refine: 1.7.1_743)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2QA8

2qa8


Resolution: 1.98→46.197 Å / SU ML: 0.48 / σ(F): 0 / Phase error: 24.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2268 1903 6.01 %RANDOM
Rwork0.181 ---
all0.1838 31685 --
obs0.1838 31685 93.05 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 42.612 Å2 / ksol: 0.312 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--2.0241 Å20 Å25.1554 Å2
2--2.7606 Å20 Å2
3----0.7364 Å2
Refinement stepCycle: LAST / Resolution: 1.98→46.197 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3845 0 50 197 4092
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074037
X-RAY DIFFRACTIONf_angle_d0.915486
X-RAY DIFFRACTIONf_dihedral_angle_d13.6841520
X-RAY DIFFRACTIONf_chiral_restr0.06643
X-RAY DIFFRACTIONf_plane_restr0.003683
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.98-2.0240.28581170.23761822X-RAY DIFFRACTION80
2.024-2.07870.33091180.20812011X-RAY DIFFRACTION88
2.0787-2.13980.27991320.21342032X-RAY DIFFRACTION90
2.1398-2.20890.28581270.20161999X-RAY DIFFRACTION88
2.2089-2.28790.32881270.22892010X-RAY DIFFRACTION88
2.2879-2.37950.23971450.19922159X-RAY DIFFRACTION94
2.3795-2.48770.26161360.18852186X-RAY DIFFRACTION97
2.4877-2.61890.22991390.18892213X-RAY DIFFRACTION97
2.6189-2.7830.21461410.19872196X-RAY DIFFRACTION96
2.783-2.99780.25891410.19352191X-RAY DIFFRACTION97
2.9978-3.29940.26491360.19042266X-RAY DIFFRACTION99
3.2994-3.77660.19391460.17112202X-RAY DIFFRACTION96
3.7766-4.75740.18141460.13862204X-RAY DIFFRACTION96
4.7574-46.1970.20741520.17992291X-RAY DIFFRACTION98
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)
12.71490.1370.65472.0954-1.22882.82670.45580.65610.0623-0.5706-0.6407-0.26050.30350.12140.1780.244-0.0465-0.00430.33980.03590.179111.47696.3159-5.4524
22.96430.1182-0.34343.5820.23062.1318-0.07620.0807-0.13790.05450.0273-0.07020.13780.09960.07840.23180.0145-0.01160.2230.01130.201115.26950.06612.7935
35.8699-0.701-0.30313.63560.3892.299-0.0141-0.11970.4583-0.0895-0.03780.0905-0.2494-0.12490.07240.25790.0255-0.01870.23460.00880.22420.693111.9044.1081
42.54230.82140.29082.7156-0.15481.84960.0149-0.3737-0.25540.1515-0.0597-0.38640.25160.20310.07970.32210.00620.00860.234-0.00780.234614.20172.428210.797
58.1275-1.2222-1.532.167-0.00633.0181-0.0897-0.44550.9057-0.2623-0.3785-0.6248-0.58990.48950.13090.3429-0.02230.00240.45870.00270.570826.906717.91662.0576
64.71332.45772.64772.77971.07014.11560.34450.0246-0.66180.26550.1524-0.14890.1353-0.1853-0.36580.29240.03520.04260.4142-0.03620.3775-2.58026.05335.9811
72.3311-0.2259-0.08463.62420.84173.7053-0.1762-0.2458-0.2210.08960.05610.10040.1577-0.03590.13920.28760.01880.03920.28280.03510.22293.60722.385732.3202
80.4030.066-1.13432.3671-3.56578.0425-0.28510.321-0.22010.45960.2033-1.1602-0.91010.62080.03090.428-0.1541-0.05890.6089-0.13160.633415.435815.555936.1252
93.86080.06650.40284.47371.61044.80820.0264-0.12110.3831-0.0049-0.02080.048-0.6764-0.04440.01350.3747-0.0107-0.00270.2884-0.01220.18531.864112.129324.4149
108.73026.54934.96418.73075.57265.76520.04850.01880.3275-0.68710.33270.28590.224-0.5666-0.50410.6545-0.04010.02510.92830.16490.52941.6698-9.377915.686
113.1322-1.34150.37983.1491-0.4743.3027-0.1188-0.12110.04910.03520.02750.0260.121-0.13430.08740.2862-0.02040.04550.2685-0.04860.2091-0.34175.797718.8232
124.9311.0997-0.05544.05462.90628.96120.0988-0.0845-0.5607-0.19240.1138-1.1354-0.00211.2494-0.36460.54440.1070.10480.54660.11160.735215.4934-5.984933.8187
133.7570.74971.44084.4345-0.41341.8697-0.0014-0.9056-0.9912-0.10370.1547-0.08950.6871-0.5532-0.18250.5771-0.03180.11020.4950.13430.48971.7789-13.585735.4658
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 304:338 )
2X-RAY DIFFRACTION2chain 'A' and (resid 339:437 )
3X-RAY DIFFRACTION3chain 'A' and (resid 438:496 )
4X-RAY DIFFRACTION4chain 'A' and (resid 497:548 )
5X-RAY DIFFRACTION5chain 'C' and (resid 687:696 )
6X-RAY DIFFRACTION6chain 'B' and (resid 305:338 )
7X-RAY DIFFRACTION7chain 'B' and (resid 339:405 )
8X-RAY DIFFRACTION8chain 'B' and (resid 406:421 )
9X-RAY DIFFRACTION9chain 'B' and (resid 422:455 )
10X-RAY DIFFRACTION10chain 'B' and (resid 456:469 )
11X-RAY DIFFRACTION11chain 'B' and (resid 470:531 )
12X-RAY DIFFRACTION12chain 'B' and (resid 532:548 )
13X-RAY DIFFRACTION13chain 'D' and (resid 688:696 )

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