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- PDB-4pxm: The Estrogen Receptor Alpha Ligand Binding Domain D538G Mutant in... -

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Basic information

Entry
Database: PDB / ID: 4pxm
TitleThe Estrogen Receptor Alpha Ligand Binding Domain D538G Mutant in Complex with Estradiol and a glucocorticoid receptor-interacting protein 1 NR box II peptide
Components
  • Estrogen receptor
  • Nuclear receptor coactivator 2
KeywordsHormone/Peptide / Metastatic Breast Cancer / Activating Mutation / ER alpha / Alpha Helical / Nuclear Hormone Receptor / Hormone-Peptide complex
Function / homology
Function and homology information


RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / steroid hormone receptor signaling pathway / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / nuclear estrogen receptor activity / Developmental Lineage of Mammary Gland Alveolar Cells / locomotor rhythm / aryl hydrocarbon receptor binding / TFIIB-class transcription factor binding / regulation of glucose metabolic process ...RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding / steroid hormone receptor signaling pathway / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / nuclear estrogen receptor activity / Developmental Lineage of Mammary Gland Alveolar Cells / locomotor rhythm / aryl hydrocarbon receptor binding / TFIIB-class transcription factor binding / regulation of glucose metabolic process / negative regulation of smooth muscle cell apoptotic process / Synthesis of bile acids and bile salts / nuclear receptor-mediated steroid hormone signaling pathway / cellular response to estrogen stimulus / Developmental Lineage of Mammary Gland Luminal Epithelial Cells / estrogen response element binding / regulation of lipid metabolic process / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Endogenous sterols / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Mitochondrial unfolded protein response (UPRmt) / Nuclear signaling by ERBB4 / estrogen receptor signaling pathway / Recycling of bile acids and salts / transcription regulator inhibitor activity / RNA polymerase II preinitiation complex assembly / cellular response to hormone stimulus / positive regulation of nitric-oxide synthase activity / steroid binding / peroxisome proliferator activated receptor signaling pathway / Regulation of lipid metabolism by PPARalpha / stem cell differentiation / protein localization to chromatin / positive regulation of adipose tissue development / bile acid and bile salt transport / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / 14-3-3 protein binding / BMAL1:CLOCK,NPAS2 activates circadian expression / regulation of cellular response to insulin stimulus / RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression / Activation of gene expression by SREBF (SREBP) / SUMOylation of transcription cofactors / Expression of BMAL (ARNTL), CLOCK, and NPAS2 / ESR-mediated signaling / negative regulation of smoothened signaling pathway / negative regulation of miRNA transcription / TBP-class protein binding / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / nuclear receptor binding / transcription corepressor binding / negative regulation of canonical NF-kappaB signal transduction / transcription coregulator binding / cellular response to estradiol stimulus / SUMOylation of intracellular receptors / circadian regulation of gene expression / Heme signaling / PPARA activates gene expression / Transcriptional activation of mitochondrial biogenesis / Cytoprotection by HMOX1 / euchromatin / Transcriptional regulation of white adipocyte differentiation / Nuclear Receptor transcription pathway / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / response to estrogen / beta-catenin binding / mRNA transcription by RNA polymerase II / nuclear receptor activity / transcription coactivator binding / positive regulation of nitric oxide biosynthetic process / transcription coregulator activity / Constitutive Signaling by Aberrant PI3K in Cancer / sequence-specific double-stranded DNA binding / phospholipase C-activating G protein-coupled receptor signaling pathway / Regulation of RUNX2 expression and activity / Ovarian tumor domain proteases / response to estradiol / PIP3 activates AKT signaling / positive regulation of cytosolic calcium ion concentration / HATs acetylate histones / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / calmodulin binding / transcription coactivator activity / Extra-nuclear estrogen signaling / protein dimerization activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin remodeling / DNA-binding transcription factor activity / negative regulation of gene expression / protein domain specific binding / chromatin binding / regulation of transcription by RNA polymerase II / regulation of DNA-templated transcription / protein kinase 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
ESTRADIOL / Estrogen receptor / Nuclear receptor coactivator 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsFanning, S.W. / Panchamukhi, S. / Greene, G.L.
CitationJournal: Elife / Year: 2016
Title: Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation.
Authors: Fanning, S.W. / Mayne, C.G. / Dharmarajan, V. / Carlson, K.E. / Martin, T.A. / Novick, S.J. / Toy, W. / Green, B. / Panchamukhi, S. / Katzenellenbogen, B.S. / Tajkhorshid, E. / Griffin, P.R. ...Authors: Fanning, S.W. / Mayne, C.G. / Dharmarajan, V. / Carlson, K.E. / Martin, T.A. / Novick, S.J. / Toy, W. / Green, B. / Panchamukhi, S. / Katzenellenbogen, B.S. / Tajkhorshid, E. / Griffin, P.R. / Shen, Y. / Chandarlapaty, S. / Katzenellenbogen, J.A. / Greene, G.L.
History
DepositionMar 24, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2016Group: Database references
Revision 1.2May 17, 2017Group: Structure summary
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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: Nuclear receptor coactivator 2
D: Nuclear receptor coactivator 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,4816
Polymers64,9364
Non-polymers5452
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6240 Å2
ΔGint-33 kcal/mol
Surface area19440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.084, 84.182, 58.372
Angle α, β, γ (deg.)90.00, 108.83, 90.00
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: 30888.252 Da / Num. of mol.: 2 / Fragment: D538G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR, ESR1, NR3A1 / Production host: Escherichia coli (E. coli) / References: UniProt: P03372
#2: Protein/peptide Nuclear receptor coactivator 2 / NCoA-2 / Class E basic helix-loop-helix protein 75 / bHLHe75 / Transcriptional intermediary factor 2 / hTIF2


Mass: 1579.866 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Peptide Synthesis / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15596
#3: Chemical ChemComp-EST / ESTRADIOL


Mass: 272.382 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24O2 / Comment: hormone*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.01 Å3/Da / Density % sol: 38.76 %
Crystal growTemperature: 298.15 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 20% PEG 3,350, 1 mM Phenylalanine, 64 mM NaCl, 50 mM MgCl2, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 298.15K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.97 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Feb 20, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.89→55.25 Å / Num. obs: 9605 / % possible obs: 99.8 % / Observed criterion σ(F): 5 / Observed criterion σ(I): 2

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASERphasing
REFMAC5.6.0117refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→55.25 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.95 / SU B: 6.743 / SU ML: 0.092 / Cross valid method: THROUGHOUT / σ(F): 5 / ESU R: 0.145 / ESU R Free: 0.133 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.21417 2018 5 %RANDOM
Rwork0.17935 ---
obs0.18112 -99.27 %-
all-40344 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.335 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å2-0 Å20.4 Å2
2--2.01 Å2-0 Å2
3----1.28 Å2
Refinement stepCycle: LAST / Resolution: 1.9→55.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3744 0 40 87 3871
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0193929
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5441.9885314
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8775473
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.66123.72164
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.28315742
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.0941523
X-RAY DIFFRACTIONr_chiral_restr0.1270.2631
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212808
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.898→1.947 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 143 -
Rwork0.236 2650 -
obs--94.77 %
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)
11.6095-0.1738-0.86340.34840.17090.7450.05690.1430.0378-0.0369-0.0183-0.0241-0.0367-0.0513-0.03850.02970.00970.00120.04680.00740.005815.11450.87515.3815
21.263-0.06660.50820.5669-0.17551.5643-0.0335-0.0424-0.02650.11950.00890.0259-0.08660.01660.02460.03990.00240.00820.0054-0.00110.00875.93472.365229.2434
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A307 - 549
2X-RAY DIFFRACTION1A2000
3X-RAY DIFFRACTION1A2101 - 2138
4X-RAY DIFFRACTION2B305 - 548
5X-RAY DIFFRACTION2B2000
6X-RAY DIFFRACTION2B2101 - 2149

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