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- PDB-4iv4: Crystal Structure of the Estrogen Receptor alpha Ligand-binding D... -

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Basic information

Entry
Database: PDB / ID: 4iv4
TitleCrystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with Constrained WAY-derivative, 5b
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 / negative regulation of miRNA transcription / SUMOylation of transcription cofactors / 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 / 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-1GS / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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: 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 1.4Sep 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
Water2,018112
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5060 Å2
ΔGint-27 kcal/mol
Surface area19800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.356, 80.508, 58.192
Angle α, β, γ (deg.)90.00, 109.84, 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-1GS / 4-[2-(2-methylpropyl)-7-(trifluoromethyl)-2H-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


Mass: 18.015 Da / Num. of mol.: 112 / 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: 39.48 %
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: 2.3→50 Å / Num. all: 21076 / Num. obs: 21076 / % possible obs: 99.06 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 9.9 % / Biso Wilson estimate: 31.42 Å2 / Rsym value: 0.138 / Net I/σ(I): 12.72
Reflection shellResolution: 2.3→2.34 Å / Redundancy: 10.2 % / Mean I/σ(I) obs: 2.83 / Rsym value: 0.751 / % possible all: 95.2

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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: 2.3→39.904 Å / SU ML: 0.56 / σ(F): 0 / Phase error: 24.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2369 1872 9.47 %RANDOM
Rwork0.1925 ---
all0.1967 19766 --
obs0.1967 19766 92.9 %-
Solvent computationShrinkage radii: 1.01 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 46.71 Å2 / ksol: 0.348 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--3.3571 Å20 Å25.1784 Å2
2--6.5742 Å2-0 Å2
3----3.2171 Å2
Refinement stepCycle: LAST / Resolution: 2.3→39.904 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3762 0 50 112 3924
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023902
X-RAY DIFFRACTIONf_angle_d0.5065285
X-RAY DIFFRACTIONf_dihedral_angle_d13.8961455
X-RAY DIFFRACTIONf_chiral_restr0.036625
X-RAY DIFFRACTIONf_plane_restr0.002650
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.3540.2651360.2251213X-RAY DIFFRACTION83
2.354-2.42330.3081280.2281323X-RAY DIFFRACTION90
2.4233-2.50150.32391370.23361306X-RAY DIFFRACTION89
2.5015-2.59090.30481540.22391309X-RAY DIFFRACTION89
2.5909-2.69460.28311310.21441342X-RAY DIFFRACTION90
2.6946-2.81720.30471310.21851302X-RAY DIFFRACTION89
2.8172-2.96570.24371480.20491377X-RAY DIFFRACTION93
2.9657-3.15140.24851470.20351432X-RAY DIFFRACTION97
3.1514-3.39460.23331510.19081443X-RAY DIFFRACTION96
3.3946-3.7360.21391420.17921408X-RAY DIFFRACTION96
3.736-4.27610.19421510.1571450X-RAY DIFFRACTION97
4.2761-5.38530.18321630.15921478X-RAY DIFFRACTION99
5.3853-39.9040.24831530.20941511X-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)
15.9162-4.2527-0.76278.07012.07716.9128-0.05340.60541.2234-0.30220.0853-0.169-0.09450.0163-0.23640.36230.01690.03090.53150.17970.45492.210933.5429-4.9856
25.77480.58930.02562.6781-1.15091.2102-0.14990.2644-1.73470.042-0.0965-0.57850.40770.26890.15020.32920.01960.0320.53760.02580.101719.39189.0176-4.9882
33.82980.1389-1.05493.12070.00162.6717-0.06910.2785-0.0542-0.20420.0105-0.0007-0.15410.01080.02660.1685-0.0108-0.03430.24660.00750.140516.459919.1821.2019
43.8489-1.2962-0.67414.2795-0.09964.2947-0.5253-0.3565-1.14910.6730.2736-0.00960.37410.2990.20730.34820.04160.05370.1980.05070.388411.7374.26127.459
56.1951.37460.40425.7641.52033.1820.12210.42640.01260.0628-0.0107-0.0277-0.1379-0.27690.13510.17220.01790.00020.26310.03770.17473.324921.89361.7824
66.1482-2.4364-1.16248.4817-0.37378.0322-0.0797-2.00641.64161.35290.50450.0062-0.36190.70380.06290.420.03060.03220.7415-0.18310.552311.110331.919215.6216
73.8112-0.38930.39572.4342-0.56172.47780.05340.09150.29630.0605-0.12760.20970.0151-0.13350.11130.24510.00060.03890.1492-0.01480.15292.656222.13558.0168
83.55651.3827-0.71894.1522-0.40285.5479-0.4727-0.8487-0.12460.56870.323-0.5880.84080.66940.08510.35440.0624-0.0640.41030.08220.409828.683119.64058.9571
94.97830.25821.62162.133-1.25595.72010.328-0.4134-1.06860.08480.50310.71230.4146-1.031-0.0280.3362-0.09050.00040.56380.0020.5919-15.814116.234525.9639
105.36612.42072.33473.40581.61144.56450.1851-0.28660.14570.2165-0.3089-0.2129-0.21880.61760.12720.3769-0.02230.01010.6148-0.00130.28219.488325.289244.7267
112.1143-0.11610.03843.55130.62284.2305-0.0672-0.2670.03330.10110.06260.10510.2080.143-0.00830.29580.04470.05670.35020.03080.21434.26718.084932.5725
123.8728-0.5150.74684.0742-0.11844.0711-0.1041-0.28420.44480.0464-0.0433-0.3122-0.58880.10160.18230.282-0.030.02880.2125-0.0220.19634.82127.768925.5067
135.83714.17963.26273.71062.58171.8995-0.4248-0.50640.4893-0.2598-0.38090.73120.33070.4178-0.06020.8345-0.00750.20090.59440.21230.5907-1.0553.128815.766
144.0669-0.6690.44742.3577-0.33963.5597-0.2176-0.203-0.00220.0196-0.01570.02960.2592-0.16380.04970.3266-0.03550.08090.2382-0.03230.19771.198620.29420.1476
155.7899-0.80550.43783.84152.09688.95490.3804-0.0508-1.03880.0171-0.0559-0.75271.79150.5804-0.02330.59280.066-0.00430.3480.03640.739613.54457.578330.6455
166.79210.8601-6.29391.245-0.66116.94620.22430.1911.4378-0.058-0.1973-0.6342-1.68850.2867-0.26670.4907-0.02860.08860.3904-0.05250.704726.860733.11112.0866
173.5391-1.59890.25754.08221.69354.6604-0.7395-1.8657-1.9820.7619-0.1216-0.62961.5197-0.20420.89760.6641-0.23330.01260.61640.15350.51282.26461.530135.4435
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resseq 305:322)
2X-RAY DIFFRACTION2chain 'A' and (resseq 323:338)
3X-RAY DIFFRACTION3chain 'A' and (resseq 339:411)
4X-RAY DIFFRACTION4chain 'A' and (resseq 412:437)
5X-RAY DIFFRACTION5chain 'A' and (resseq 438:455)
6X-RAY DIFFRACTION6chain 'A' and (resseq 456:472)
7X-RAY DIFFRACTION7chain 'A' and (resseq 473:530)
8X-RAY DIFFRACTION8chain 'A' and (resseq 531:548)
9X-RAY DIFFRACTION9chain 'B' and (resseq 305:322)
10X-RAY DIFFRACTION10chain 'B' and (resseq 323:338)
11X-RAY DIFFRACTION11chain 'B' and (resseq 339:411)
12X-RAY DIFFRACTION12chain 'B' and (resseq 412:455)
13X-RAY DIFFRACTION13chain 'B' and (resseq 456:470)
14X-RAY DIFFRACTION14chain 'B' and (resseq 471:537)
15X-RAY DIFFRACTION15chain 'B' and (resseq 538:548)
16X-RAY DIFFRACTION16chain 'C' and (resseq 687:696)
17X-RAY DIFFRACTION17chain 'D' and (resseq 688:696)

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