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- PDB-1l2i: Human Estrogen Receptor alpha Ligand-binding Domain in Complex wi... -

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Entry
Database: PDB / ID: 1l2i
TitleHuman Estrogen Receptor alpha Ligand-binding Domain in Complex with (R,R)-5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol and a Glucocorticoid Receptor Interacting Protein 1 NR box II Peptide
Components
  • ESTROGEN RECEPTOR
  • GLUCOCORTICOID RECEPTOR-INTERACTING PROTEIN 1
KeywordsTRANSCRIPTION RECEPTOR/COACTIVATOR / nuclear receptor / transcription factor / estrogen / agonist / coactivator / TRANSCRIPTION RECEPTOR-COACTIVATOR COMPLEX
Function / homology
Function and homology information


Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Recycling of bile acids and salts / Synthesis of bile acids and bile salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / HATs acetylate histones / Regulation of lipid metabolism by PPARalpha / Cytoprotection by HMOX1 / Estrogen-dependent gene expression ...Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Recycling of bile acids and salts / Synthesis of bile acids and bile salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / HATs acetylate histones / Regulation of lipid metabolism by PPARalpha / Cytoprotection by HMOX1 / Estrogen-dependent gene expression / regulation of epithelial cell apoptotic process / RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / antral ovarian follicle growth / 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 / nuclear estrogen receptor activity / epithelial cell development / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / locomotor rhythm / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / aryl hydrocarbon receptor binding / vagina development / 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 / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / Mitochondrial unfolded protein response (UPRmt) / nuclear receptor-mediated steroid hormone signaling pathway / Nuclear signaling by ERBB4 / transcription regulator inhibitor activity / RNA polymerase II preinitiation complex assembly / positive regulation of DNA-binding transcription factor activity / positive regulation of nitric-oxide synthase activity / estrogen receptor signaling pathway / positive regulation of adipose tissue development / protein localization to chromatin / steroid binding / 14-3-3 protein binding / peroxisome proliferator activated receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / regulation of cellular response to insulin stimulus / negative regulation of DNA-binding transcription factor activity / negative regulation of miRNA transcription / response to progesterone / nitric-oxide synthase regulator activity / ESR-mediated signaling / TBP-class protein binding / transcription coregulator binding / nuclear estrogen receptor binding / nuclear receptor binding / transcription corepressor binding / negative regulation of smoothened signaling pathway / stem cell differentiation / cellular response to estradiol stimulus / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / circadian regulation of gene expression / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / response to estrogen / Regulation of RUNX2 expression and activity / transcription coactivator binding / circadian rhythm / nuclear receptor activity / Ovarian tumor domain proteases / positive regulation of fibroblast proliferation / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of nitric oxide biosynthetic process / sequence-specific double-stranded DNA binding / response to estradiol / PIP3 activates AKT signaling / regulation of gene expression / positive regulation of cytosolic calcium ion concentration / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / DNA-binding transcription activator activity, RNA polymerase II-specific / regulation of inflammatory response / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / transcription regulator complex / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription coactivator activity / Extra-nuclear estrogen 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 / Nuclear receptor coactivators bHLH domain / 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-ETC / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsShiau, A.K. / Barstad, D. / Radek, J.T. / Meyers, M.J. / Nettles, K.W. / Katzenellenbogen, B.S. / Katzenellenbogen, J.A. / Agard, D.A. / Greene, G.L.
Citation
Journal: Nat.Struct.Biol. / Year: 2002
Title: Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism.
Authors: Shiau, A.K. / Barstad, D. / Radek, J.T. / Meyers, M.J. / Nettles, K.W. / Katzenellenbogen, B.S. / Katzenellenbogen, J.A. / Agard, D.A. / Greene, G.L.
#1: Journal: Cell(Cambridge,Mass.) / Year: 1998
Title: The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of this Interaction by Tamoxifen
Authors: Shiau, A.K. / Barstad, D. / Loria, P.M. / Cheng, L. / Kushner, P.J. / Agard, D.A. / Greene, G.L.
#2: Journal: J.Med.Chem. / Year: 1999
Title: Estrogen Receptor Subtype-selective Ligands: Asymmetric Synthesis and Biological Evaluation of cis- and trans-5,11-dialkyl-5,6,11,12-tetrahydrochrysenes
Authors: Meyers, M.J. / Sun, J. / Carlson, K.E. / Katzenellenbogen, B.S. / Katzenellenbogen, J.A.
History
DepositionFeb 21, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jul 24, 2019Group: Data collection / Derived calculations / Refinement description
Category: software / struct_conn
Item: _software.name / _software.version / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Aug 16, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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: GLUCOCORTICOID RECEPTOR-INTERACTING PROTEIN 1
D: GLUCOCORTICOID RECEPTOR-INTERACTING PROTEIN 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,6537
Polymers62,9764
Non-polymers6763
Water2,990166
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6250 Å2
ΔGint-34 kcal/mol
Surface area19670 Å2
MethodPISA
2
A: ESTROGEN RECEPTOR
C: GLUCOCORTICOID RECEPTOR-INTERACTING PROTEIN 1
hetero molecules

B: ESTROGEN RECEPTOR
D: GLUCOCORTICOID RECEPTOR-INTERACTING PROTEIN 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,6537
Polymers62,9764
Non-polymers6763
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_554x,y,z-11
Buried area4870 Å2
ΔGint-37 kcal/mol
Surface area21050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.545, 82.600, 59.040
Angle α, β, γ (deg.)90.00, 111.53, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein ESTROGEN RECEPTOR / ER-ALPHA / OESTROGEN RECEPTOR ALPHA


Mass: 29908.256 Da / Num. of mol.: 2 / Fragment: ligand-binding domain (residues 297-554)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pET23D / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)pLysS / References: UniProt: P03372
#2: Protein/peptide GLUCOCORTICOID RECEPTOR-INTERACTING PROTEIN 1 / NUCLEAR RECEPTOR COACTIVATOR 2 / GRIP1


Mass: 1579.866 Da / Num. of mol.: 2 / Fragment: NR box II (residues 686-698) / Source method: obtained synthetically
Details: The peptide was chemically synthesized. This sequence occurs naturally in mice.
References: UniProt: Q61026
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-ETC / (R,R)-5,11-CIS-DIETHYL-5,6,11,12-TETRAHYDROCHRYSENE-2,8-DIOL


Mass: 320.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24O2 / Comment: antagonist*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 166 / 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: 1.96 Å3/Da / Density % sol: 43.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.8
Details: 16% (w/v) PEG 4000, 50 mM Magnesium chloride, 53 mM Tris pH 8.8 292-294 K, VAPOR DIFFUSION, HANGING DROP, temperature 293K
Crystal grow
*PLUS
Temperature: 19-21 ℃
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
15.0 mg/mlprotein1drop
216 %(w/v)PEG40001reservoir
353 mMTris-HCl1reservoirpH8.8
450 mM1reservoirMgCl2

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Data collection

DiffractionMean temperature: 103 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 24, 1999
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 1.95→46.8 Å / Num. all: 34533 / Num. obs: 34533 / % possible obs: 97.9 % / Observed criterion σ(I): -3 / Redundancy: 3.5 % / Biso Wilson estimate: 25.2 Å2 / Rsym value: 0.065 / Net I/σ(I): 18.8
Reflection shellResolution: 1.95→2.02 Å / Mean I/σ(I) obs: 2.9 / Num. unique all: 3432 / Rsym value: 0.531 / % possible all: 97.7
Reflection
*PLUS
Num. measured all: 119409 / Rmerge(I) obs: 0.065
Reflection shell
*PLUS
% possible obs: 97.7 % / Rmerge(I) obs: 0.531

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Processing

Software
NameVersionClassification
CNS1refinement
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3ERD

3erd


Resolution: 1.95→46.8 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 10000 / Isotropic thermal model: Restrained / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.243 2304 6.5 %Random
Rwork0.203 ---
all-34533 --
obs-34533 97.1 %-
Solvent computationSolvent model: flat model / Bsol: 61.9288 Å2 / ksol: 0.360796 e/Å3
Displacement parametersBiso mean: 38.53 Å2
Baniso -1Baniso -2Baniso -3
1--6.164 Å20 Å2-4.135 Å2
2--0.138 Å20 Å2
3---6.026 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.27 Å0.25 Å
Refinement stepCycle: LAST / Resolution: 1.95→46.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3828 0 49 166 4043
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg1.08
X-RAY DIFFRACTIONc_dihedral_angle_d17.99
X-RAY DIFFRACTIONc_improper_angle_d0.72
X-RAY DIFFRACTIONc_mcbond_it2.9751.5
X-RAY DIFFRACTIONc_scbond_it4.3782
X-RAY DIFFRACTIONc_mcangle_it3.9252
X-RAY DIFFRACTIONc_scangle_it6.2232.5
LS refinement shellResolution: 1.95→2.02 Å / Rfactor Rfree error: 0.024 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.3359 201 5.7 %
Rwork0.2964 2986 -
obs-3187 90.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
Refinement
*PLUS
Rfactor obs: 0.203 / Rfactor Rfree: 0.243 / Rfactor Rwork: 0.203
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg17.99
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.72
LS refinement shell
*PLUS
Rfactor Rfree: 0.336 / Rfactor Rwork: 0.296 / Rfactor obs: 0.296

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