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- PDB-4iv2: Crystal Structure of the Estrogen Receptor alpha Ligand-binding D... -

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Basic information

Entry
Database: PDB / ID: 4iv2
TitleCrystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with Dynamic WAY-derivative, 5a
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 / 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 / prostate epithelial cord elongation / epithelial cell development / locomotor rhythm / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / aryl hydrocarbon receptor binding / androgen metabolic process / TFIIB-class transcription factor binding / regulation of lipid metabolic process / steroid hormone mediated signaling pathway / cellular response to Thyroglobulin triiodothyronine / regulation of glucose metabolic process / Synthesis of bile acids and bile salts / mammary gland alveolus development / intracellular estrogen receptor signaling pathway / cellular response to estrogen stimulus / Endogenous sterols / estrogen response element binding / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / positive regulation of phospholipase C activity / intracellular steroid hormone receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / cellular response to hormone stimulus / protein localization to chromatin / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / Regulation of lipid metabolism by PPARalpha / steroid binding / nitric-oxide synthase regulator activity / ESR-mediated signaling / BMAL1:CLOCK,NPAS2 activates circadian gene expression / 14-3-3 protein binding / transcription corepressor binding / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / negative regulation of miRNA transcription / response to progesterone / cellular response to estradiol stimulus / nuclear estrogen receptor binding / transcription coregulator binding / stem cell differentiation / nuclear receptor binding / positive regulation of nitric-oxide synthase activity / circadian regulation of gene expression / Heme signaling / euchromatin / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Transcriptional activation of mitochondrial biogenesis / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / beta-catenin binding / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / response to estrogen / RNA polymerase II transcription regulator complex / male gonad development / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of nitric oxide biosynthetic process / nuclear receptor activity / positive regulation of DNA-binding transcription factor activity / positive regulation of fibroblast proliferation / Ovarian tumor domain proteases / Circadian Clock / sequence-specific double-stranded DNA binding / response to estradiol / PIP3 activates AKT signaling / phospholipase C-activating G protein-coupled receptor signaling pathway / HATs acetylate histones / ATPase binding / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / regulation of inflammatory response / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
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 / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Nuclear receptor coactivator, interlocking / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / 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-1GR / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.14 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 22, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Feb 26, 2020Group: Data collection / Database references / Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / reflns_shell / struct_ref_seq_dif
Item: _reflns_shell.pdbx_Rsym_value / _struct_ref_seq_dif.details
Revision 1.4Sep 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)59,6326
Polymers58,9324
Non-polymers7012
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5200 Å2
ΔGint-27 kcal/mol
Surface area20330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.235, 80.813, 57.897
Angle α, β, γ (deg.)90.00, 109.81, 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-1GR / 4-[1-(2-methylpropyl)-7-(trifluoromethyl)-1H-indazol-3-yl]benzene-1,3-diol


Mass: 350.335 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17F3N2O2
#4: Water ChemComp-HOH / water / 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: 2.03 Å3/Da / Density % sol: 39.28 %
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: Dec 14, 2011
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: 1.9→50 Å / Num. all: 25549 / Num. obs: 25549 / % possible obs: 98.21 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.4 % / Biso Wilson estimate: 31.67 Å2 / Rsym value: 0.073 / Net I/σ(I): 10.89
Reflection shellResolution: 1.9→1.93 Å / Redundancy: 3.2 % / Mean I/σ(I) obs: 2.06 / % possible all: 95.12

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Processing

Software
NameVersionClassification
Blu-Iceicedata 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: 2.14→39.829 Å / SU ML: 0.59 / σ(F): 0 / Phase error: 22.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2256 1319 5.44 %Random
Rwork0.1775 ---
all0.1801 24264 --
obs0.1801 24264 93.27 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 45.732 Å2 / ksol: 0.331 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--2.1215 Å20 Å23.0025 Å2
2--3.8134 Å2-0 Å2
3----1.6919 Å2
Refinement stepCycle: LAST / Resolution: 2.14→39.829 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3841 0 50 161 4052
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044013
X-RAY DIFFRACTIONf_angle_d0.7285446
X-RAY DIFFRACTIONf_dihedral_angle_d14.4651504
X-RAY DIFFRACTIONf_chiral_restr0.051637
X-RAY DIFFRACTIONf_plane_restr0.002674
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.14-2.22570.27621170.23122246X-RAY DIFFRACTION82
2.2257-2.3270.28291460.19972404X-RAY DIFFRACTION89
2.327-2.44960.20451410.18982487X-RAY DIFFRACTION92
2.4496-2.60310.26661360.19152566X-RAY DIFFRACTION93
2.6031-2.8040.26031560.20182496X-RAY DIFFRACTION92
2.804-3.08610.24641570.19582638X-RAY DIFFRACTION97
3.0861-3.53240.23271520.17862683X-RAY DIFFRACTION98
3.5324-4.44950.18711520.14692675X-RAY DIFFRACTION97
4.4495-39.8290.20781620.17012750X-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)
15.4191-3.71150.44366.9034-0.4782.45230.34530.64820.6885-0.6449-0.3577-0.4411-0.0909-0.27330.04930.2025-0.0664-0.00270.38360.05630.23738.587426.1741-6.7454
23.13940.0573-0.70573.5640.66032.3948-0.1232-0.0183-0.17210.20210.0502-0.14370.22420.12860.06380.22090.0206-0.00860.24180.00940.181815.714814.93832.3082
34.7968-0.0344-0.55491.99070.1791.75740.0102-0.28190.1490.0732-0.01720.03350.04610.01010.00850.22750.01170.0190.1839-0.01530.14967.922721.88937.2402
45.2074-0.04542.56871.3877-0.12994.86590.0578-0.0024-0.84120.03750.2559-0.1494-0.1313-0.2227-0.28230.28350.03010.06550.3231-0.03450.2868-0.609221.551535.7113
51.6641-0.09330.20494.75641.28394.2945-0.0779-0.05380.0401-0.12630.0544-0.0444-0.02610.06280.06950.2449-0.0180.01540.25330.02180.16465.332319.434931.9017
63.3157-0.30880.81341.8553-0.21174.07830.06040.0464-0.03450.0128-0.065-0.01970.072-0.02360.04170.2216-0.01280.04940.2132-0.02960.1592.46520.101421.6289
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 305:332)
2X-RAY DIFFRACTION2(chain A and resid 333:436)
3X-RAY DIFFRACTION3(chain A and resid 437:548)
4X-RAY DIFFRACTION4(chain B and resid 305:341)
5X-RAY DIFFRACTION5(chain B and resid 342:421)
6X-RAY DIFFRACTION6(chain B and resid 422:548)

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