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- PDB-4iw8: Crystal Structure of the Estrogen Receptor alpha Ligand-binding D... -

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Basic information

Entry
Database: PDB / ID: 4iw8
TitleCrystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with Dynamic WAY-derivative, 9a
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 / 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-KN3 / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.0375 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: 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 / struct_ref_seq_dif
Item: _reflns.number_all / _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
D: Nuclear receptor coactivator 2
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,6566
Polymers58,9324
Non-polymers7252
Water2,972165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5260 Å2
ΔGint-31 kcal/mol
Surface area20460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.170, 81.094, 58.119
Angle α, β, γ (deg.)90.00, 109.49, 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-KN3 / 4-[1-(3-methylbut-2-en-1-yl)-7-(trifluoromethyl)-1H-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.: 165 / 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: 2.04 Å3/Da / Density % sol: 39.77 %
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: 2.0375→50 Å / Num. obs: 29476 / % possible obs: 97.12 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 6.3 % / Biso Wilson estimate: 33.72 Å2 / Rsym value: 0.117 / Net I/σ(I): 14.53
Reflection shellResolution: 2.0375→2.09 Å / Redundancy: 6.2 % / Mean I/σ(I) obs: 2.3 / Rsym value: 0.812 / % possible all: 89.33

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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: 2.0375→45.735 Å / SU ML: 0.58 / σ(F): 0 / Phase error: 27.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2468 1874 6.78 %Random
Rwork0.2081 ---
all0.2108 27626 --
obs0.2108 27626 91.02 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 43.154 Å2 / ksol: 0.296 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--1.79 Å20 Å20.5104 Å2
2--4.064 Å2-0 Å2
3----2.274 Å2
Refinement stepCycle: LAST / Resolution: 2.0375→45.735 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3917 0 52 165 4134
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024079
X-RAY DIFFRACTIONf_angle_d0.5535524
X-RAY DIFFRACTIONf_dihedral_angle_d14.3651541
X-RAY DIFFRACTIONf_chiral_restr0.039641
X-RAY DIFFRACTIONf_plane_restr0.002677
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0375-2.09260.3691080.29481587X-RAY DIFFRACTION73
2.0926-2.15420.29721400.26641799X-RAY DIFFRACTION84
2.1542-2.22370.27261360.25191752X-RAY DIFFRACTION81
2.2237-2.30320.35631300.27711875X-RAY DIFFRACTION87
2.3032-2.39540.28291540.23062029X-RAY DIFFRACTION93
2.3954-2.50440.27961490.2192045X-RAY DIFFRACTION94
2.5044-2.63640.27061440.2312088X-RAY DIFFRACTION95
2.6364-2.80160.29361490.22091996X-RAY DIFFRACTION93
2.8016-3.01780.27431590.21082110X-RAY DIFFRACTION97
3.0178-3.32150.24971540.21352120X-RAY DIFFRACTION98
3.3215-3.80190.21121540.18432085X-RAY DIFFRACTION95
3.8019-4.78910.1691440.16282095X-RAY DIFFRACTION95
4.7891-45.74620.25131530.21152171X-RAY DIFFRACTION97
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)
10.0066-0.06120.05570.6541-0.4440.21310.36050.2854-0.31410.41690.24110.2960.0335-0.15830.02340.40990.08320.02170.80390.01210.5481-30.84617.08220.7832
21.6576-0.2906-0.26241.2539-0.41071.9543-0.1009-0.2411-0.07680.0343-0.04590.021-0.01770.15340.00010.4269-0.01780.01180.41580.03770.3289-12.318116.83236.8494
30.0831-0.08270.10270.2226-0.04810.1237-0.0614-0.43590.72440.42340.3503-0.3079-0.5973-0.04040.00760.6109-0.07180.01620.4416-0.00060.4827-8.050532.72588.4641
40.87920.02630.02880.45290.08860.1802-0.40170.950.3134-0.6106-0.1365-0.758-0.85370.5547-0.00830.5685-0.16960.01830.49970.02280.5599-2.847529.7676-0.5038
50.06260.0099-0.03840.0519-0.0190.0368-0.4589-0.0674-0.00110.1975-0.066-0.0958-0.50770.26690.00130.72210.21190.04820.6016-0.00180.5486-18.428834.9345-4.4467
60.50270.04420.59040.2927-0.2710.83770.43640.41680.0442-0.7334-0.3081-0.18510.003-0.656400.3697-0.01410.00530.4858-0.01140.3586-21.256320.1496-4.1876
70.20420.05790.25750.00340.10890.57870.65690.40611.2831-0.3256-0.03330.1639-1.1148-0.4670.74611.62990.4430.78921.45730.27910.9507-16.64491.1189-12.9515
80.0816-0.0941-0.02350.32520.08860.01810.7517-0.0836-0.35550.66430.4645-0.03910.747-0.44720.00120.8448-0.12480.07670.54710.03530.766-22.96273.2716-12.1466
90.6092-0.1027-0.15370.4899-0.25762.38880.0911-0.0693-0.018-0.0043-0.0330.01130.0560.0299-00.301-0.0273-0.00330.3546-0.03880.3443-13.645719.2177-5.2229
101.40350.3651-0.32040.586-0.44651.14740.26780.29640.6255-0.2997-0.2494-0.4764-0.0466-0.1310.00930.18390.009-0.00360.23940.0180.2079-10.189727.894-33.1979
110.82790.58030.26530.5920.22850.3169-0.58750.1158-0.0043-0.1610.4861-0.2911-0.33560.11550.00080.46070.04520.01080.341-0.0060.53517.99262.6335-28.6764
120.9978-0.1094-0.47420.76990.14470.7137-0.02850.00410.0343-0.1120.0404-0.11170.02360.06310.02840.17960.00910.00340.1512-0.00360.1561-1.882118.1119-26.1631
131.6033-0.3745-0.50540.09170.11910.16160.3997-0.4872-0.10720.48180.005-0.48770.10830.462-0.01191.0340.439-0.96651.0678-0.5140.57411.78532.8066-15.6428
141.2245-0.1845-0.20040.38440.3880.774-0.0087-0.0099-0.06250.1075-0.08190.0120.1464-0.03040.01960.2122-0.00120.01070.190.00320.2116-12.71716.0673-23.1755
151.31351.24210.92391.62951.56731.6826-0.4777-0.99121.3172-0.1520.11831.0509-0.6805-0.1601-0.22080.6652-0.30890.56940.9049-0.32951.3272-11.268435.8269-15.7185
16-0.045-0.0295-0.05171.09740.18010.36210.07640.18780.06580.0077-0.13950.09050.15460.08-0.09120.18140.0125-0.0010.19120.01260.1726-16.437620.6389-19.7767
172.0030.5828-0.99270.65910.23731.08150.7911-0.2608-0.1168-0.18830.17090.45230.32740.57840.42060.6750.3349-0.02810.77750.31170.690114.194411.3812-15.136
182.9316-0.26811.68720.47190.23371.3079-0.2711-0.60820.4281-0.0262-0.1851-0.4496-0.09610.4559-0.5650.27750.06380.07510.35290.03810.296510.513920.6831-18.9719
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 305:326)
2X-RAY DIFFRACTION2(chain A and resid 327:396)
3X-RAY DIFFRACTION3(chain A and resid 397:413)
4X-RAY DIFFRACTION4(chain A and resid 414:434)
5X-RAY DIFFRACTION5(chain A and resid 435:439)
6X-RAY DIFFRACTION6(chain A and resid 440:458)
7X-RAY DIFFRACTION7(chain A and resid 459:467)
8X-RAY DIFFRACTION8(chain A and resid 468:475)
9X-RAY DIFFRACTION9(chain A and resid 476:548)
10X-RAY DIFFRACTION10(chain B and resid 304:330)
11X-RAY DIFFRACTION11(chain B and resid 331:345)
12X-RAY DIFFRACTION12(chain B and resid 346:417)
13X-RAY DIFFRACTION13(chain B and resid 418:423)
14X-RAY DIFFRACTION14(chain B and resid 424:458)
15X-RAY DIFFRACTION15(chain B and resid 459:477)
16X-RAY DIFFRACTION16(chain B and resid 478:526)
17X-RAY DIFFRACTION17(chain B and resid 527:533)
18X-RAY DIFFRACTION18(chain B and resid 534:548)

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