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- PDB-2qgw: Crystal Structure of the Estrogen Receptor Alpha Ligand Binding D... -

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Entry
Database: PDB / ID: 2qgw
TitleCrystal Structure of the Estrogen Receptor Alpha Ligand Binding Domain Complexed with a Chloro-Indazole Compound
Components
  • Estrogen receptor
  • Nuclear receptor coactivator 2
KeywordsTRANSCRIPTION / Protein-Ligand 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 / steroid hormone receptor signaling pathway / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / locomotor rhythm / mammary gland branching involved in pregnancy / uterus development / negative regulation of smooth muscle cell apoptotic process / aryl hydrocarbon receptor binding / vagina development / TFIIB-class transcription factor binding / cellular response to Thyroglobulin triiodothyronine / regulation of lipid metabolic process / 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 / positive regulation of DNA-binding transcription factor activity / negative regulation of DNA-binding transcription factor activity / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / transcription regulator inhibitor activity / positive regulation of nitric-oxide synthase activity / estrogen receptor signaling pathway / protein localization to chromatin / steroid binding / positive regulation of adipose tissue development / 14-3-3 protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / negative regulation of canonical NF-kappaB signal transduction / peroxisome proliferator activated receptor signaling pathway / regulation of cellular response to insulin stimulus / response to progesterone / ESR-mediated signaling / negative regulation of miRNA transcription / TBP-class protein binding / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / nuclear receptor binding / transcription corepressor binding / transcription coregulator binding / negative regulation of smoothened signaling pathway / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / euchromatin / circadian rhythm / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / RNA polymerase II transcription regulator complex / transcription coactivator binding / male gonad development / nuclear receptor activity / positive regulation of fibroblast proliferation / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of RUNX2 expression and activity / positive regulation of nitric oxide biosynthetic process / sequence-specific double-stranded DNA binding / Ovarian tumor domain proteases / response to estradiol / PIP3 activates AKT signaling / positive regulation of cytosolic calcium ion concentration / ATPase binding / regulation of gene expression / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of inflammatory response / DNA-binding transcription activator activity, RNA polymerase II-specific / 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 / calmodulin binding
Similarity search - Function
Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / Estrogen receptor/oestrogen-related receptor / Nuclear receptor coactivator, DUF1518 ...Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2/3, DUF4927 / Domain of unknown function (DUF4927) / Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / 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
3-CHLORO-2-(4-HYDROXYPHENYL)-2H-INDAZOL-5-OL / Estrogen receptor / Nuclear receptor coactivator 2 / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.39 Å
AuthorsNettles, K.W. / Bruning, J.B. / Nowak, J. / Sharma, S.K. / Hahm, J.B. / Shi, Y. / Kulp, K. / Hochberg, R.B. / Zhou, H. / Katzenellenbogen, J.A. ...Nettles, K.W. / Bruning, J.B. / Nowak, J. / Sharma, S.K. / Hahm, J.B. / Shi, Y. / Kulp, K. / Hochberg, R.B. / Zhou, H. / Katzenellenbogen, J.A. / Katzenellenbogen, B.S. / Kim, Y. / Joachmiak, A. / Greene, G.L.
CitationJournal: Nat.Chem.Biol. / Year: 2008
Title: NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses
Authors: Nettles, K.W. / Bruning, J.B. / Gil, G. / Nowak, J. / Sharma, S.K. / Hahm, J.B. / Kulp, K. / Hochberg, R.B. / Zhou, H. / Katzenellenbogen, J.A. / Katzenellenbogen, B.S. / Kim, Y. / Joachmiak, A. / Greene, G.L.
History
DepositionJun 29, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 18, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Source and taxonomy
Category: database_2 / pdbx_entity_src_syn ...database_2 / pdbx_entity_src_syn / 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 / _pdbx_entity_src_syn.details / _pdbx_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_common_name / _pdbx_entity_src_syn.organism_scientific / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)62,4546
Polymers61,9334
Non-polymers5212
Water3,891216
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5340 Å2
ΔGint-31.2 kcal/mol
Surface area20820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.053, 84.266, 58.213
Angle α, β, γ (deg.)90.000, 108.480, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Estrogen receptor / ER / Estradiol receptor / ER-alpha


Mass: 29386.609 Da / Num. of mol.: 2 / Fragment: Steroid-binding region, residues 298-554 / Mutation: Y537S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Plasmid: pMCSG7 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) Rosetta / References: UniProt: P03372
#2: Protein/peptide Nuclear receptor coactivator 2


Mass: 1579.866 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Mus musculus (house mouse) / References: UniProt: Q8BN74, UniProt: Q61026*PLUS
#3: Chemical ChemComp-EES / 3-CHLORO-2-(4-HYDROXYPHENYL)-2H-INDAZOL-5-OL


Mass: 260.676 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H9ClN2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 216 / 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: 2.1 Å3/Da / Density % sol: 41.56 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.97934 Å
DetectorType: SBC / Detector: CCD / Details: mirrors
RadiationMonochromator: Rosenbaum-Rock double-crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97934 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. all: 20938 / Num. obs: 20938 / % possible obs: 95.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Biso Wilson estimate: 30.69 Å2 / Rmerge(I) obs: 0.097 / Rsym value: 0.097 / Χ2: 0.594 / Net I/σ(I): 4.7
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.415 / Mean I/σ(I) obs: 1.8 / Num. unique all: 2028 / Rsym value: 0.415 / Χ2: 0.447 / % possible all: 93.6

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT2data extraction
HKL-2000data collection
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3ERD

3erd


Resolution: 2.39→33.37 Å / Cor.coef. Fo:Fc: 0.897 / Cor.coef. Fo:Fc free: 0.798 / SU B: 24.276 / SU ML: 0.304 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 8.6 / ESU R Free: 0.375 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.296 920 5.1 %RANDOM
Rwork0.238 ---
obs0.241 17913 87.46 %-
all-17913 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.294 Å2
Baniso -1Baniso -2Baniso -3
1-0.64 Å20 Å21.03 Å2
2--0.41 Å20 Å2
3----0.39 Å2
Refinement stepCycle: LAST / Resolution: 2.39→33.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3982 0 36 216 4234
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0214092
X-RAY DIFFRACTIONr_bond_other_d0.0010.022751
X-RAY DIFFRACTIONr_angle_refined_deg1.3411.9935526
X-RAY DIFFRACTIONr_angle_other_deg1.02536751
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1675492
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.8324.07172
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.72115783
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.3691524
X-RAY DIFFRACTIONr_chiral_restr0.1050.2646
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.024369
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02767
X-RAY DIFFRACTIONr_nbd_refined0.2060.21029
X-RAY DIFFRACTIONr_nbd_other0.1940.22796
X-RAY DIFFRACTIONr_nbtor_refined0.1710.21950
X-RAY DIFFRACTIONr_nbtor_other0.0880.22017
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.670.2176
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.4620.214
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2890.230
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1340.22
X-RAY DIFFRACTIONr_mcbond_it0.8811.53257
X-RAY DIFFRACTIONr_mcbond_other0.1011.5996
X-RAY DIFFRACTIONr_mcangle_it0.97223996
X-RAY DIFFRACTIONr_scbond_it1.13431814
X-RAY DIFFRACTIONr_scangle_it1.6134.51530
LS refinement shellResolution: 2.39→2.45 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 82 -
Rwork0.215 1361 -
obs-1443 95.75 %
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)
10.64560.0001-0.02790.9415-0.11691.1177-0.017-0.0419-0.04590.1302-0.0425-0.0106-0.04720.01330.0595-0.1715-0.00250.0172-0.1587-0.0025-0.18436.4441.272229.5242
21.0696-0.2468-0.55390.41770.05661.09180.07890.03210.0819-0.0612-0.0397-0.0381-0.0554-0.0228-0.0392-0.1731-0.00280.0084-0.18680.0084-0.185614.54570.29015.6577
330.5412-4.379419.351619.0585-5.559612.68240.67790.586-1.29041.43880.0914-1.02051.18410.0525-0.76930.06770.0614-0.1002-0.1373-0.0079-0.219211.5472-16.649138.8859
45.32885.725-6.024137.6758-9.49727.10040.65670.680.3315-0.0008-0.8867-1.9884-0.10970.48930.23-0.2164-0.00180.0383-0.21840.0171-0.085224.91616.65250.9481
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA305 - 5489 - 252
2X-RAY DIFFRACTION2BB305 - 5489 - 252
3X-RAY DIFFRACTION3CC687 - 6962 - 11
4X-RAY DIFFRACTION4DD688 - 6963 - 11

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