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- PDB-4zn9: Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) i... -

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Basic information

Entry
Database: PDB / ID: 4zn9
TitleCrystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in complex with Oxabicyclic Heptene Sulfonate (OBHS)
Components
  • Estrogen receptor
  • Nuclear receptor-interacting peptide
KeywordsTRANSCRIPTION / protein ligand complex
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 / nuclear estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis ...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 / nuclear estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / epithelial cell development / mammary gland branching involved in pregnancy / locomotor rhythm / uterus development / negative regulation of smooth muscle cell apoptotic process / vagina development / aryl hydrocarbon receptor binding / TFIIB-class transcription factor binding / cellular response to Thyroglobulin triiodothyronine / regulation of lipid metabolic process / steroid hormone receptor signaling pathway / 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 / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / cellular response to hormone stimulus / Recycling of bile acids and salts / negative regulation of canonical NF-kappaB signal transduction / estrogen receptor signaling pathway / positive regulation of adipose tissue development / protein localization to chromatin / : / steroid binding / 14-3-3 protein binding / Regulation of lipid metabolism by PPARalpha / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / peroxisome proliferator activated receptor signaling pathway / TBP-class protein binding / regulation of cellular response to insulin stimulus / nitric-oxide synthase regulator activity / BMAL1:CLOCK,NPAS2 activates circadian expression / negative regulation of miRNA transcription / positive regulation of nitric-oxide synthase activity / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / ESR-mediated signaling / : / transcription coregulator binding / response to progesterone / nuclear receptor binding / transcription corepressor binding / nuclear estrogen receptor binding / positive regulation of DNA-binding transcription factor activity / stem cell differentiation / cellular response to estradiol stimulus / SUMOylation of intracellular receptors / circadian regulation of gene expression / negative regulation of DNA-binding transcription factor activity / mRNA transcription by RNA polymerase II / transcription coactivator binding / Heme signaling / Transcriptional activation of mitochondrial biogenesis / euchromatin / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / PPARA activates gene expression / Cytoprotection by HMOX1 / beta-catenin binding / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / response to estrogen / nuclear receptor activity / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of fibroblast proliferation / male gonad development / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / : / PIP3 activates AKT signaling / response to estradiol / HATs acetylate histones / 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 / positive regulation of cytosolic calcium ion concentration / DNA-binding transcription activator activity, RNA polymerase II-specific / regulation of inflammatory response
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 / 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
Chem-OBH / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.215 Å
AuthorsNwachukwu, J.C. / Srinivasan, S. / Zheng, Y. / Wang, S. / Min, J. / Dong, C. / Liao, Z. / Cavett, V. / Nowak, J. / Houtman, R. ...Nwachukwu, J.C. / Srinivasan, S. / Zheng, Y. / Wang, S. / Min, J. / Dong, C. / Liao, Z. / Cavett, V. / Nowak, J. / Houtman, R. / Carlson, K.E. / Josan, J.S. / Elemento, O. / Katzenellenbogen, J.A. / Zhou, H.B. / Nettles, K.W.
Citation
Journal: Chemmedchem / Year: 2012
Title: Development of selective estrogen receptor modulator (SERM)-like activity through an indirect mechanism of estrogen receptor antagonism: defining the binding mode of 7-oxabicyclo[2.2.1]hept-5- ...Title: Development of selective estrogen receptor modulator (SERM)-like activity through an indirect mechanism of estrogen receptor antagonism: defining the binding mode of 7-oxabicyclo[2.2.1]hept-5-ene scaffold core ligands.
Authors: Zheng, Y. / Zhu, M. / Srinivasan, S. / Nwachukwu, J.C. / Cavett, V. / Min, J. / Carlson, K.E. / Wang, P. / Dong, C. / Katzenellenbogen, J.A. / Nettles, K.W. / Zhou, H.B.
#1: Journal: ChemMedChem / Year: 2012
Title: Development of selective estrogen receptor modulator (SERM)-like activity through an indirect mechanism of estrogen receptor antagonism: defining the binding mode of 7-oxabicyclo[2.2.1]hept-5- ...Title: Development of selective estrogen receptor modulator (SERM)-like activity through an indirect mechanism of estrogen receptor antagonism: defining the binding mode of 7-oxabicyclo[2.2.1]hept-5-ene scaffold core ligands.
Authors: Zheng, Y. / Zhu, M. / Srinivasan, S. / Nwachukwu, J.C. / Cavett, V. / Min, J. / Carlson, K.E. / Wang, P. / Dong, C. / Katzenellenbogen, J.A. / Nettles, K.W. / Zhou, H.B.
History
DepositionMay 4, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 9, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_prerelease_seq / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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-interacting peptide
D: Nuclear receptor-interacting peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,6966
Polymers61,8194
Non-polymers8772
Water4,360242
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5900 Å2
ΔGint-30 kcal/mol
Surface area20110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.110, 83.250, 58.730
Angle α, β, γ (deg.)90.000, 109.840, 90.000
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: 29329.457 Da / Num. of mol.: 2 / Fragment: ligand-binding domain, UNP residues 301-559 / Mutation: Y537S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P03372
#2: Protein/peptide Nuclear receptor-interacting peptide / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1579.866 Da / Num. of mol.: 2 / Fragment: UNP residues 686-698 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-OBH / cyclohexa-2,5-dien-1-yl (1S,2R,4S)-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonate


Mass: 438.493 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H22O6S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 242 / 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: 43.34 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 8.3 / Details: 15% PEG 3350, 0.05M MgCl2, 0.067M NaCl, 0.1M Tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.9 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 20, 2009
RadiationMonochromator: Side scattering bent cube i-beam single crystal, assymetric cut 4.965 degs
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 30690 / % possible obs: 88 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.093 / Χ2: 2.136 / Net I/av σ(I): 29.385 / Net I/σ(I): 11.6 / Num. measured all: 170857
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2-2.072.20.514460.88741.9
2.07-2.152.60.46321151.13360.7
2.15-2.253.30.4528701.14982.4
2.25-2.374.20.433051.23694.9
2.37-2.525.20.34234211.41299.5
2.52-2.716.20.27834791.579100
2.71-2.996.90.20734991.834100
2.99-3.427.40.14334792.516100
3.42-4.317.20.07735133.063100
4.31-506.90.04935633.06799.9

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.215→46.031 Å / FOM work R set: 0.811 / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2417 1289 5.11 %
Rwork0.2213 23958 -
obs0.2224 25247 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 78.32 Å2 / Biso mean: 36.59 Å2 / Biso min: 9.73 Å2
Refinement stepCycle: final / Resolution: 2.215→46.031 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3872 0 62 242 4176
Biso mean--38.83 34.49 -
Num. residues----491
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0054080
X-RAY DIFFRACTIONf_angle_d1.4285540
X-RAY DIFFRACTIONf_chiral_restr0.079650
X-RAY DIFFRACTIONf_plane_restr0.006689
X-RAY DIFFRACTIONf_dihedral_angle_d13.7291533
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Highest resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.215-2.3041126255897
2.3041-2.4090.34811400.3352676100
2.409-2.5361382689100
2.536-2.69480.3191420.27242637100
2.6948-2.90290.32171380.26482672100
2.9029-3.19490.25911490.22912660100
3.1949-3.65710.22281550.20262670100
3.6571-4.60690.18241580.17112669100
4.60690.2241430.18572727100
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)
10.1089-0.2742-0.00610.6095-0.06930.4833-0.1016-0.07880.03260.1030.15540.2181-0.04230.02380.54420.0356-0.0964-0.07760.0915-0.1739-0.01682.6480.860632.2385
20.5888-0.2598-0.08080.2681-0.02620.58580.0763-0.0793-0.02460.1347-0.00740.1166-0.0167-0.1344-00.1814-0.00030.00760.21820.00240.2275-1.9267-0.331524.5324
30.34650.0564-0.11380.21010.05930.33560.08930.0586-0.0941-0.1657-0.1129-0.2319-0.00130.177-0.00820.17030.02140.00080.2205-0.00610.2598.3918-3.51120.425
41.3931-0.4053-0.03051.0127-0.03740.36980.1017-0.2690.4339-0.3224-0.1045-0.245-0.12640.1135-0.04180.02560.0268-0.03810.1476-0.00730.096115.54530.987218.5216
50.8393-0.0461-0.05961.46371.71732.02850.15480.36620.2757-0.47010.1010.0851-0.6866-0.1485-0.00270.12870.0535-0.02820.3293-0.02540.3737-12.60625.278614.2384
60.44770.4682-0.06720.60380.23640.4253-0.0358-0.0818-0.2986-0.39980.41250.1518-0.1799-0.05980.00890.4443-0.00830.16030.4512-0.03390.425518.29391.6679-8.9059
70.1990.2720.01590.33870.02220.0403-0.42680.3463-0.0564-0.40950.3314-0.0789-0.121-0.1332-0.00880.5726-0.05480.01450.4075-0.0070.24177.6139-0.2066-11.6305
80.41490.2855-0.07030.3490.34460.7764-0.17680.3564-0.123-0.40170.24410.2049-0.1026-0.1837-0.87340.23-0.05880.0836-0.17970.3461-0.55819.65063.4097-4.3103
90.04-0.0465-0.02540.06450.00530.03640.05310.16670.4495-0.17990.0605-0.16-0.31730.0268-00.49180.0516-0.02610.2528-0.03240.34649.138713.59642.4959
100.03940.00050.03550.00150.0140.0660.18-0.12920.0941-0.0012-0.1375-0.1770.1220.14030.00010.3171-0.02050.07480.27390.0170.259819.4707-0.18432.8443
110.06530.03250.01190.48550.07650.15270.04550.067-0.0493-0.173-0.0887-0.30610.14560.1320.0033-0.07930.08340.1480.12750.08320.219126.7072-3.12588.9132
120.0187-0.0102-0.05460.1676-0.06130.1868-0.1187-0.14670.3783-0.1136-0.02110.0332-0.2546-0.18410.00130.21660.024-0.01430.2330.00050.188712.97134.84579.2862
130.0226-0.0058-0.02710.20460.00780.0111-0.256-0.0502-0.08220.1316-0.00880.7989-0.039-0.60690.00130.6913-0.0711-0.05890.6917-0.0440.5064-5.4133-4.6389-5.164
140.07010.0598-0.00580.0831-0.0048-0.00040.0779-0.0470.31970.1288-0.08110.0358-0.2298-0.02460.00080.37340.0427-0.04520.4307-0.05590.5556-7.284718.360726.3013
150.0082-0.0015-0.00530.00050.00130.00440.04290.0181-0.21890.1275-0.02250.18340.2299-0.0149-0.00010.9392-0.0673-0.02590.3498-0.1130.52796.9298-16.7517-10.8041
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 305 through 338 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 339 through 420 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 421 through 473 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 474 through 525 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 526 through 554 )A0
6X-RAY DIFFRACTION6chain 'B' and (resid 305 through 338 )B0
7X-RAY DIFFRACTION7chain 'B' and (resid 339 through 363 )B0
8X-RAY DIFFRACTION8chain 'B' and (resid 364 through 420 )B0
9X-RAY DIFFRACTION9chain 'B' and (resid 421 through 438 )B0
10X-RAY DIFFRACTION10chain 'B' and (resid 439 through 473 )B0
11X-RAY DIFFRACTION11chain 'B' and (resid 474 through 496 )B0
12X-RAY DIFFRACTION12chain 'B' and (resid 497 through 525 )B0
13X-RAY DIFFRACTION13chain 'B' and (resid 526 through 554 )B0
14X-RAY DIFFRACTION14chain 'C' and (resid 687 through 696 )C0
15X-RAY DIFFRACTION15chain 'D' and (resid 687 through 695 )D0

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