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

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Basic information

Entry
Database: PDB / ID: 4iwc
TitleCrystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with a Dynamic Thiophene-derivative
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 / Mitochondrial unfolded protein response (UPRmt) / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / nuclear receptor-mediated steroid hormone signaling pathway / positive regulation of DNA-binding transcription factor activity / negative 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 / : / steroid binding / positive regulation of adipose tissue development / 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 / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / 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 / PPARA activates gene expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / 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 / 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) / Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / Estrogen receptor/oestrogen-related receptor / Nuclear receptor coactivator, DUF1518 ...Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / 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
4,4'-thiene-2,5-diylbis(3-methylphenol) / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.24 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
B: Estrogen receptor
C: Nuclear receptor coactivator 2
D: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,5246
Polymers58,9324
Non-polymers5932
Water3,207178
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5180 Å2
ΔGint-30 kcal/mol
Surface area20130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.864, 83.501, 58.610
Angle α, β, γ (deg.)90.00, 108.54, 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-1GV / 4,4'-thiene-2,5-diylbis(3-methylphenol)


Mass: 296.383 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H16O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / 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: 2.2 Å3/Da / Density % sol: 44.07 %
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: APS / Beamline: 23-ID-B / Wavelength: 1 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Dec 18, 2010
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.24→50 Å / Num. all: 23428 / Num. obs: 23428 / % possible obs: 95.13 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.1 % / Rsym value: 0.089 / Net I/σ(I): 14.8
Reflection shellResolution: 2.24→2.28 Å / Redundancy: 2.1 % / Mean I/σ(I) obs: 4.57 / Rsym value: 0.239 / % possible all: 75.6

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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: 2.24→46.411 Å / SU ML: 0.53 / σ(F): 0 / Phase error: 23.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2267 1907 8.59 %
Rwork0.1851 --
obs0.1887 22209 90.18 %
all-22209 -
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 37.224 Å2 / ksol: 0.321 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--2.0533 Å20 Å24.371 Å2
2--8.5425 Å2-0 Å2
3----6.4891 Å2
Refinement stepCycle: LAST / Resolution: 2.24→46.411 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3911 0 42 178 4131
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024043
X-RAY DIFFRACTIONf_angle_d1.2725468
X-RAY DIFFRACTIONf_dihedral_angle_d16.0161508
X-RAY DIFFRACTIONf_chiral_restr0.052640
X-RAY DIFFRACTIONf_plane_restr0.003679
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.24-2.29620.2826920.22241007X-RAY DIFFRACTION64
2.2962-2.35830.2821210.22161202X-RAY DIFFRACTION75
2.3583-2.42770.311170.20441355X-RAY DIFFRACTION83
2.4277-2.5060.2081300.18731347X-RAY DIFFRACTION86
2.506-2.59560.26171330.20141415X-RAY DIFFRACTION89
2.5956-2.69950.26651340.19621456X-RAY DIFFRACTION91
2.6995-2.82230.21991390.20651497X-RAY DIFFRACTION93
2.8223-2.97110.25011410.20061535X-RAY DIFFRACTION95
2.9711-3.15720.25531400.19261525X-RAY DIFFRACTION96
3.1572-3.40090.20621520.19291557X-RAY DIFFRACTION97
3.4009-3.7430.22151460.1721594X-RAY DIFFRACTION98
3.743-4.28430.1861550.15731580X-RAY DIFFRACTION99
4.2843-5.39650.19111510.1571604X-RAY DIFFRACTION99
5.3965-46.42110.24261560.19941628X-RAY DIFFRACTION99
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)
10.41240.11820.07790.74190.29810.1178-0.1377-0.38310.06660.13390.08390.28980.0262-0.03870.00120.1708-0.00690.0010.28450.0120.19090.2396-1.276230.1627
20.39960.0434-0.06040.46-0.17190.2256-0.0021-0.1060.05940.13580.03270.0369-0.1289-0.06760.05250.09110.02640.02660.09080.00780.09350.47270.077324.9131
30.60740.3301-0.4790.5118-0.12460.5473-0.0096-0.01830.0093-0.0043-0.0038-0.01620.02550.0386-0.01590.09340.0047-0.01290.10740.00330.09947.57240.256618.1506
40.42930.39530.27490.42680.17360.380.06250.3694-0.1688-0.31730.0278-0.10280.05970.20440.04240.30410.00040.01340.46070.01370.221618.55320.467-9.4591
50.86670.33220.56490.46370.07630.4901-0.13680.1090.0085-0.11220.12410.0526-0.0033-0.0414-0.04670.23180.01790.00550.12120.03210.11079.46393.47-5.2559
60.19230.1546-0.05220.6040.21630.5286-0.097-0.0125-0.0171-0.09780.0126-0.16140.07670.0289-0.130.0874-0.01560.01030.09330.01580.087114.1606-2.6024.5927
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 305:347)
2X-RAY DIFFRACTION2(chain A and resid 348:417)
3X-RAY DIFFRACTION3(chain A and resid 418:548)
4X-RAY DIFFRACTION4(chain B and resid 305:339)
5X-RAY DIFFRACTION5(chain B and resid 340:437)
6X-RAY DIFFRACTION6(chain B and resid 438:549)

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