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- PDB-2qab: Crystal Structure of Estrogen Receptor Alpha Ligand Binding Domai... -

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Basic information

Entry
Database: PDB / ID: 2qab
TitleCrystal Structure of Estrogen Receptor Alpha Ligand Binding Domain Mutant 537S Complexed with an Ethyl 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 / 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 / locomotor rhythm / negative regulation of smooth muscle cell apoptotic process / uterus development / mammary gland branching involved in pregnancy / vagina development / aryl hydrocarbon receptor binding / TFIIB-class transcription factor binding / cellular response to Thyroglobulin triiodothyronine / steroid hormone receptor signaling pathway / regulation of lipid metabolic process / androgen metabolic process / regulation of glucose metabolic process / cellular response to estrogen stimulus / mammary gland alveolus development / estrogen response element binding / Mitochondrial unfolded protein response (UPRmt) / nuclear receptor-mediated steroid hormone signaling pathway / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / protein localization to chromatin / estrogen receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / positive regulation of adipose tissue development / steroid binding / 14-3-3 protein binding / 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 / positive regulation of nitric-oxide synthase activity / negative regulation of miRNA transcription / ESR-mediated signaling / positive regulation of DNA-binding transcription factor activity / transcription coregulator binding / response to progesterone / transcription corepressor binding / nuclear receptor binding / nuclear estrogen receptor binding / negative regulation of DNA-binding transcription factor activity / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / transcription coactivator binding / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / RNA polymerase II transcription regulator complex / response to estrogen / nuclear receptor activity / circadian rhythm / positive regulation of fibroblast proliferation / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / response to estradiol / PIP3 activates AKT signaling / ATPase binding / regulation of gene expression / positive regulation of cytosolic calcium ion concentration / DNA-binding transcription activator activity, RNA polymerase II-specific / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / 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 / transcription coactivator activity / DNA-binding transcription factor activity, RNA polymerase II-specific / Extra-nuclear estrogen signaling / calmodulin binding
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
3-ETHYL-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: 1.89 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 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 1.4Feb 21, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_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)62,4426
Polymers61,9334
Non-polymers5092
Water28816
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5260 Å2
ΔGint-30.4 kcal/mol
Surface area20980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.824, 83.080, 58.304
Angle α, β, γ (deg.)90.000, 109.130, 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: 5

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LEULEUARGARGAA306 - 54810 - 252
21LEULEUARGARGBB306 - 54810 - 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: 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-EI1 / 3-ETHYL-2-(4-HYDROXYPHENYL)-2H-INDAZOL-5-OL


Mass: 254.284 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H14N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / 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: 2.06 Å3/Da / Density % sol: 40.35 %
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: 14-BM-C / Wavelength: 0.97934 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Details: bent conical Si-mirror (Rh coating)
RadiationMonochromator: bent cylindrical Ge(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97934 Å / Relative weight: 1
ReflectionResolution: 1.86→50 Å / Num. all: 41242 / Num. obs: 41242 / % possible obs: 98.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 31.89 Å2 / Rmerge(I) obs: 0.098 / Rsym value: 0.098 / Χ2: 4.972 / Net I/σ(I): 13.8
Reflection shellResolution: 1.86→1.93 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.688 / Mean I/σ(I) obs: 1.91 / Num. unique all: 4019 / Rsym value: 0.688 / Χ2: 2.383 / % possible all: 95.9

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.2.0005refinement
PDB_EXTRACT2data extraction
HKL-2000data collection
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.89→19.54 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.917 / SU B: 11.79 / SU ML: 0.153 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.19 / ESU R Free: 0.172
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27 2012 5.1 %RANDOM
Rwork0.224 ---
obs0.226 39668 98.59 %-
all-39668 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.174 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20 Å20.05 Å2
2---0.01 Å20 Å2
3----0.07 Å2
Refinement stepCycle: LAST / Resolution: 1.89→19.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4007 0 38 16 4061
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0214164
X-RAY DIFFRACTIONr_angle_refined_deg1.0511.9875628
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6115496
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.74723.933178
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.32715796
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2971524
X-RAY DIFFRACTIONr_chiral_restr0.0710.2659
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022998
X-RAY DIFFRACTIONr_nbd_refined0.2230.32101
X-RAY DIFFRACTIONr_nbtor_refined0.3150.52875
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1460.5219
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3060.355
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4220.56
X-RAY DIFFRACTIONr_mcbond_it3.0441.52587
X-RAY DIFFRACTIONr_mcangle_it4.00924050
X-RAY DIFFRACTIONr_scbond_it6.32331787
X-RAY DIFFRACTIONr_scangle_it8.674.51578
Refine LS restraints NCS

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

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A932MEDIUM POSITIONAL0.180.5
1A925LOOSE POSITIONAL0.535
1A932MEDIUM THERMAL2.432
1A925LOOSE THERMAL4.2110
2C36MEDIUM POSITIONAL0.20.5
2C43LOOSE POSITIONAL0.815
2C36MEDIUM THERMAL3.072
2C43LOOSE THERMAL4.9110
LS refinement shellResolution: 1.89→1.939 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 153 -
Rwork0.324 2717 -
obs-2870 98.09 %
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)
11.7757-0.41660.36671.7675-0.27862.3047-0.0947-0.1172-0.03750.2180.0232-0.112-0.1240.03930.0716-0.16560.01390.0332-0.2276-0.0011-0.19595.71580.637629.2748
22.8681-0.1244-0.24971.1959-0.03571.67790.03620.1390.1113-0.0603-0.021-0.0956-0.1351-0.0425-0.0152-0.1777-0.00560.0019-0.2430.0051-0.250613.85320.36025.5733
327.68473.594615.479521.25280.823910.32660.6163-0.6565-1.82240.8887-0.1346-0.8631.3343-0.0828-0.48170.23070.0896-0.0073-0.13910.1039-0.076810.5024-17.056838.6898
439.472-1.53796.997734.7229-1.552612.53840.24570.7921.4891-0.6841-0.4868-1.2043-0.06340.93840.2412-0.08550.01480.1911-0.31740.1059-0.061524.050516.23930.5103
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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