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- PDB-2qa8: Crystal Structure of the Estrogen Receptor Alpha Ligand Binding D... -

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Basic information

Entry
Database: PDB / ID: 2qa8
TitleCrystal Structure of the Estrogen Receptor Alpha Ligand Binding Domain Mutant 537S Complexed with Genistein
Components
  • (Estrogen receptor) x 2
  • 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 / G protein-coupled estrogen receptor activity / 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 / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / response to estrogen / circadian rhythm / nuclear receptor activity / positive regulation of fibroblast proliferation / male gonad development / 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 / 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
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
GENISTEIN / 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: 1.85 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 14, 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 20, 2021Group: Database references / Derived calculations / Source and taxonomy
Category: database_2 / pdbx_entity_src_syn ...database_2 / pdbx_entity_src_syn / struct_conn / 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id
Revision 1.4Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)62,6266
Polymers62,0854
Non-polymers5402
Water1,26170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6540 Å2
ΔGint-29.8 kcal/mol
Surface area19380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.668, 77.957, 58.000
Angle α, β, γ (deg.)90.000, 109.050, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22D

NCS domain segments:

Component-ID: 1 / Refine code: 4

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERARGARGAA305 - 5489 - 252
21SERSERARGARGBB305 - 5489 - 252
12LYSLYSASPASPCC688 - 6963 - 11
22LYSLYSASPASPDD688 - 6963 - 11

NCS ensembles :
ID
1
2

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Components

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


Mass: 29462.727 Da / Num. of mol.: 1 / 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 Estrogen receptor / ER / Estradiol receptor / ER-alpha


Mass: 29462.727 Da / Num. of mol.: 1 / 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
#3: 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
#4: Chemical ChemComp-GEN / GENISTEIN / 5,7-DIHYDROXY-3-(4-HYDROXYPHENYL)-4H-1-BENZOPYRAN-4-ONE / 4',5,7-TRIHYDROXYISOFLAVONE / PRUNETOL / GENISTEOL


Mass: 270.237 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H10O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 70 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 1.92 Å3/Da / Density % sol: 35.79 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: VAPOR DIFFUSION, HANGING DROP, temperature 298K, pH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97934 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 8, 2004 / Details: Rosenbaum-Rock vertical focusing mirror
RadiationMonochromator: Rosenbaum-Rock high-resolution double-crystal monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97934 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. all: 38560 / Num. obs: 38560 / % possible obs: 97 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.1 % / Biso Wilson estimate: 26.39 Å2 / Rmerge(I) obs: 0.049 / Rsym value: 0.049 / Net I/σ(I): 20.78
Reflection shellResolution: 1.85→1.901 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.367 / Mean I/σ(I) obs: 1.79 / Num. unique all: 2204 / Rsym value: 0.367 / % possible all: 76.29

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0005refinement
PDB_EXTRACT2data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3ERD

3erd


Resolution: 1.85→19.89 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.917 / SU B: 13.391 / SU ML: 0.178 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.178 / ESU R Free: 0.167
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.264 1935 5 %RANDOM
Rwork0.211 ---
obs0.214 38516 96.85 %-
all-38516 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 48.196 Å2
Baniso -1Baniso -2Baniso -3
1-0.16 Å20 Å2-0.01 Å2
2---0.18 Å20 Å2
3---0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.85→19.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3882 0 40 70 3992
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0214015
X-RAY DIFFRACTIONr_angle_refined_deg1.2781.9985417
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8145477
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.49824.176170
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.89115775
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.921523
X-RAY DIFFRACTIONr_chiral_restr0.0860.2636
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022868
X-RAY DIFFRACTIONr_nbd_refined0.2440.32026
X-RAY DIFFRACTIONr_nbtor_refined0.3160.52769
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2080.5263
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2890.357
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1940.55
X-RAY DIFFRACTIONr_mcbond_it3.6461.52494
X-RAY DIFFRACTIONr_mcangle_it4.97923891
X-RAY DIFFRACTIONr_scbond_it8.36931752
X-RAY DIFFRACTIONr_scangle_it11.1124.51526
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A1779MEDIUM POSITIONAL0.490.5
1A1779MEDIUM THERMAL3.972
2C79MEDIUM POSITIONAL0.60.5
2C79MEDIUM THERMAL5.282
LS refinement shellResolution: 1.85→1.901 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.428 110 -
Rwork0.351 2094 -
obs-2204 76.29 %
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)
12.61590.0874-0.26351.1009-0.00441.27430.0288-0.04130.13670.0246-0.0110.0484-0.06880.0514-0.0178-0.3160.00650.0005-0.3719-0.0076-0.34314.40580.222421.4517
21.5446-0.00270.84471.4622-0.11113.1584-0.0015-0.0867-0.0762-0.20290.03720.07960.0716-0.2565-0.0358-0.2874-0.0070.0214-0.3420.0149-0.299911.45790.7956-2.2301
324.1251-1.4566-5.730421.159112.415114.14140.0723-0.56852.3148-0.0983-0.09790.8773-0.6654-1.14540.0256-0.15650.02050.0372-0.15730.02120.1112-6.763416.894425.6223
423.6152-0.98122.23947.08883.0751.63630.36071.2229-1.7097-0.5115-0.18870.37281.26990.0372-0.1720.3217-0.1031-0.08150.1207-0.00050.19537.4735-16.5311-11.5388
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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