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

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Basic information

Entry
Database: PDB / ID: 4iwf
TitleCrystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with a Dynamic Oxime-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 / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / 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 / 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 / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / 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 / 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 / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / aryl hydrocarbon receptor binding / TFIIB-class transcription factor binding / regulation of lipid metabolic process / androgen 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 / estrogen receptor signaling pathway / 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 / regulation of cellular response to insulin stimulus / Recycling of bile acids and salts / cellular response to hormone stimulus / protein localization to chromatin / 14-3-3 protein binding / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / TBP-class protein binding / nitric-oxide synthase regulator activity / steroid binding / Regulation of lipid metabolism by PPARalpha / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / ESR-mediated signaling / transcription corepressor binding / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / positive regulation of nitric-oxide synthase activity / cellular response to estradiol stimulus / transcription coregulator binding / response to progesterone / stem cell differentiation / nuclear estrogen receptor binding / nuclear receptor binding / circadian regulation of gene expression / Heme signaling / SUMOylation of intracellular receptors / euchromatin / 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 / PPARA activates gene expression / Cytoprotection by HMOX1 / beta-catenin binding / transcription coactivator binding / positive regulation of DNA-binding transcription factor activity / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / response to estrogen / RNA polymerase II transcription regulator complex / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / male gonad development / positive regulation of nitric oxide biosynthetic process / sequence-specific double-stranded DNA binding / positive regulation of fibroblast proliferation / Ovarian tumor domain proteases / Circadian Clock / PIP3 activates AKT signaling / response to estradiol / phospholipase C-activating G protein-coupled receptor signaling pathway / HATs acetylate histones / positive regulation of cytosolic calcium ion concentration / ATPase binding / regulation of inflammatory response / fibroblast proliferation / 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 / Nuclear receptor coactivator, interlocking / 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. / 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-15Q / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.932 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: Advisory / Database references / Derived calculations
Category: pdbx_distant_solvent_atoms / pdbx_struct_assembly ...pdbx_distant_solvent_atoms / 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)59,4956
Polymers58,9324
Non-polymers5632
Water4,378243
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5290 Å2
ΔGint-29 kcal/mol
Surface area19480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.897, 83.036, 58.191
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-15Q / 2-chloro-3'-fluoro-3-[(E)-(hydroxyimino)methyl]biphenyl-4,4'-diol


Mass: 281.667 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H9ClFNO3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 243 / 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: 2.17 Å3/Da / Density % sol: 43.39 %
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: 1.93→50 Å / Num. all: 36045 / Num. obs: 36045 / % possible obs: 95.24 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.6 % / Biso Wilson estimate: 30.81 Å2 / Rsym value: 0.05 / Net I/σ(I): 21.17
Reflection shellResolution: 1.93→1.96 Å / Redundancy: 3 % / Mean I/σ(I) obs: 4.32 / Rsym value: 0.287 / % possible all: 74.65

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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: 1.932→40.419 Å / SU ML: 0.18 / σ(F): 0 / Phase error: 25.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2086 1905 5.51 %
Rwork0.1727 --
obs0.1747 34548 91.36 %
all-34550 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--8.0369 Å20 Å26.9423 Å2
2--16.4824 Å2-0 Å2
3----8.4455 Å2
Refinement stepCycle: LAST / Resolution: 1.932→40.419 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3831 0 38 243 4112
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084005
X-RAY DIFFRACTIONf_angle_d1.0635419
X-RAY DIFFRACTIONf_dihedral_angle_d14.6091500
X-RAY DIFFRACTIONf_chiral_restr0.062632
X-RAY DIFFRACTIONf_plane_restr0.004669
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.932-1.98030.2953820.21741581X-RAY DIFFRACTION63
1.9803-2.03380.26261190.21851918X-RAY DIFFRACTION76
2.0338-2.09370.2371170.20062046X-RAY DIFFRACTION80
2.0937-2.16120.2481260.1952248X-RAY DIFFRACTION88
2.1612-2.23850.22871310.19472329X-RAY DIFFRACTION92
2.2385-2.32810.25051540.17962414X-RAY DIFFRACTION95
2.3281-2.4340.23141390.17862479X-RAY DIFFRACTION97
2.434-2.56240.25751420.17912477X-RAY DIFFRACTION98
2.5624-2.72290.2221510.18342499X-RAY DIFFRACTION98
2.7229-2.9330.25611500.18412522X-RAY DIFFRACTION99
2.933-3.22810.21571440.1832524X-RAY DIFFRACTION99
3.2281-3.69490.21341460.16762521X-RAY DIFFRACTION99
3.6949-4.65410.17141550.1412542X-RAY DIFFRACTION99
4.6541-40.4190.1721490.17272543X-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)
14.35660.37950.20851.29270.5542.68290.0916-0.58170.85840.51430.2522-0.5779-0.3870.5629-0.38640.4773-0.1101-0.03690.6242-0.14710.530418.878110.386431.5607
20.40240.4093-0.47853.0819-0.70271.00910.1878-0.8475-0.25390.3586-0.23520.2820.2891-0.11760.13090.3985-0.03320.08790.49740.05530.3344-7.2869-7.46932.3371
36.18992.44110.61473.64141.78569.8129-0.4667-0.1421-0.3912-0.1407-0.2761-0.49780.39570.32680.53450.23470.02230.05420.40550.10160.4476-14.9212-9.877120.6633
42.39410.326-0.48232.57510.05512.01840.0423-0.16650.00080.1645-0.04490.0584-0.0363-0.1685-0.01370.25120.01820.01540.29820.01610.22170.2588-2.475723.0754
53.0555-0.5273-0.01063.849-0.26841.7599-0.0723-0.2325-0.15980.00010.0731-0.1481-0.0331-0.0452-0.00960.224-0.01060.00060.3176-0.00230.241212.7695-0.116821.9373
62.17330.62390.49390.4498-0.30860.83420.35560.05030.6376-0.4150.1049-0.3315-0.0988-0.1333-0.53911.23080.1654-0.03670.7952-0.14890.77449.595418.717714.0219
73.4114-0.4073-0.47132.7092-0.14942.38690.1045-0.5190.32050.1248-0.2046-0.3814-0.22150.19960.08650.2448-0.0135-0.02140.3156-0.01420.298323.14852.519821.0802
85.681-0.0746-1.13170.7146-0.20090.5492-0.06210.1711-0.0358-0.07250.10490.27690.0406-0.235-0.07010.2186-0.0035-0.00480.30440.03950.2493-2.9352-2.180412.7983
95.47920.2227-0.26654.49410.81415.02640.06880.48011.0119-0.2873-0.21290.39290.1667-0.19960.36220.30970.0314-0.0670.3395-0.02790.4521-10.16877.087318.2186
105.92330.04373.1473.2845-0.54384.08770.12140.9422-0.7135-0.63650.138-0.26440.00710.6671-0.32650.424-0.07250.12940.5248-0.09570.338123.6982-2.366-7.1119
117.3188-2.3194.09139.5804-2.35428.2325-0.89630.62410.8164-0.427-0.29450.9757-0.792-0.25231.14110.91170.0507-0.40420.5588-0.11280.8116-3.185710.679-14.4638
122.58150.51520.882.96420.63033.1866-0.1950.2120.0185-0.37450.11140.2696-0.2680.06780.08480.3519-0.0247-0.00070.22880.00170.21879.46812.6854-5.0833
132.1396-0.00420.41832.63930.11942.1724-0.06630.09750.1140.10350.0394-0.0244-0.21270.25730.02730.3012-0.03310.00580.26180.0190.250819.38522.61372.8022
142.00152.82480.6142.0510.54355.5425-0.231-0.6908-0.8950.08460.2459-0.54241.1525-0.72410.0580.4593-0.05980.05850.5096-0.00650.559618.4452-14.39099.182
152.24920.3530.32331.3696-0.02021.07930.0116-0.20450.0470.0045-0.0225-0.3769-0.05920.3408-0.02570.2283-0.0234-0.00780.30480.01550.342727.47712.979810.873
165.95260.24631.96013.21640.39894.23120.25030.41420.33930.108-0.08760.45560.1886-0.2639-0.09950.23010.05020.01150.31560.02470.27073.21391.8813.6305
177.6429-1.7369-0.33925.93280.42833.44820.02490.74681.0433-0.5195-0.24280.31990.0049-0.08030.19840.48360.0762-0.22491.39670.03940.6806-10.17090.1244-7.7049
184.3993-0.0898-1.15893.5304-0.09764.67250.0836-0.0004-0.18360.1086-0.45220.6071-0.4517-0.4970.6090.4853-0.048-0.12530.41640.00090.4431-1.7296-7.0941-7.2989
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 305:320)
2X-RAY DIFFRACTION2(chain A and resid 321:337)
3X-RAY DIFFRACTION3(chain A and resid 338:343)
4X-RAY DIFFRACTION4(chain A and resid 344:435)
5X-RAY DIFFRACTION5(chain A and resid 436:459)
6X-RAY DIFFRACTION6(chain A and resid 460:472)
7X-RAY DIFFRACTION7(chain A and resid 473:507)
8X-RAY DIFFRACTION8(chain A and resid 508:534)
9X-RAY DIFFRACTION9(chain A and resid 535:548)
10X-RAY DIFFRACTION10(chain B and resid 306:331)
11X-RAY DIFFRACTION11(chain B and resid 332:343)
12X-RAY DIFFRACTION12(chain B and resid 344:434)
13X-RAY DIFFRACTION13(chain B and resid 435:458)
14X-RAY DIFFRACTION14(chain B and resid 459:478)
15X-RAY DIFFRACTION15(chain B and resid 479:509)
16X-RAY DIFFRACTION16(chain B and resid 510:526)
17X-RAY DIFFRACTION17(chain B and resid 527:533)
18X-RAY DIFFRACTION18(chain B and resid 534:548)

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