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- PDB-7y8f: Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Com... -

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Basic information

Entry
Database: PDB / ID: 7y8f
TitleEstrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with an Inhibitor 30o and GRIP Peptide
Components
  • Estrogen receptor
  • Grip peptide
KeywordsTRANSCRIPTION/INHIBITOR / Complex / Inhibitor / Estrogen Receptor Alpha / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of branching involved in prostate gland morphogenesis / prostate epithelial cord elongation / 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 ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of branching involved in prostate gland morphogenesis / prostate epithelial cord elongation / 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 proliferation involved in mammary gland duct elongation / epithelial cell development / vagina development / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / TFIIB-class transcription factor binding / androgen metabolic process / steroid hormone receptor signaling pathway / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / nuclear receptor-mediated steroid hormone signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / 14-3-3 protein binding / protein localization to chromatin / estrogen receptor signaling pathway / steroid binding / nitric-oxide synthase regulator activity / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / ESR-mediated signaling / transcription corepressor binding / negative regulation of miRNA transcription / positive regulation of nitric-oxide synthase activity / cellular response to estradiol stimulus / transcription coregulator binding / stem cell differentiation / nuclear estrogen receptor binding / positive regulation of DNA-binding transcription factor activity / SUMOylation of intracellular receptors / euchromatin / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / nuclear receptor activity / Regulation of RUNX2 expression and activity / positive regulation of fibroblast proliferation / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / phospholipase C-activating G protein-coupled receptor signaling pathway / ATPase binding / regulation of inflammatory response / positive regulation of cytosolic calcium ion concentration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / fibroblast proliferation / DNA-binding transcription activator activity, RNA polymerase II-specific / Estrogen-dependent gene expression / transcription regulator complex / Extra-nuclear estrogen signaling / calmodulin binding / DNA-binding transcription factor activity, RNA polymerase II-specific / chromatin remodeling / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of gene expression / chromatin binding / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of DNA-templated transcription / Golgi apparatus / negative regulation of transcription by RNA polymerase II / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding / membrane / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
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 hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type ...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 hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / 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
Similarity search - Domain/homology
Chem-IC7 / DI(HYDROXYETHYL)ETHER / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsMin, J. / Hu, H.B. / Yang, Y. / Dong, C.E. / Zhou, H.B. / Chen, C.-C. / Guo, R.-T.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82103994 China
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Structure-guided identification of novel dual-targeting estrogen receptor alpha degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer.
Authors: Xin, L. / Min, J. / Hu, H. / Li, Y. / Du, C. / Xie, B. / Cheng, Y. / Deng, X. / Deng, X. / Shen, K. / Huang, J. / Chen, C.C. / Guo, R.T. / Dong, C. / Zhou, H.B.
History
DepositionJun 23, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.2Nov 29, 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
C: Grip peptide
B: Estrogen receptor
D: Grip peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,8507
Polymers60,0934
Non-polymers7583
Water2,990166
1
A: Estrogen receptor
C: Grip peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1523
Polymers30,0462
Non-polymers1061
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1320 Å2
ΔGint-6 kcal/mol
Surface area11480 Å2
MethodPISA
2
B: Estrogen receptor
D: Grip peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6984
Polymers30,0462
Non-polymers6522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-23 kcal/mol
Surface area11430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.741, 101.584, 195.304
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#1: Protein Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 29081.109 Da / Num. of mol.: 2 / Fragment: Ligand Binding Domain / Mutation: Y537S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P03372
#2: Protein/peptide Grip peptide


Mass: 965.194 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 4 types, 169 molecules

#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-IC7 / [4-(trifluoromethyl)phenyl] (1~{S},2~{R},4~{S})-5-(4-hydroxyphenyl)-6-[4-(1,2,4-triazol-1-yl)phenyl]-7-oxabicyclo[2.2.1]heptane-2-sulfonate


Mass: 555.525 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H20F3N3O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: 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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Details

Has ligand of interestY

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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: 2.18 Å3/Da / Density % sol: 43.49 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 18% (w/v) PEG 3350, 0.25 M Ammonium sulfate, and 0.1 M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: LIQUID ANODE / Type: BRUKER METALJET / Wavelength: 1.34138 Å
DetectorType: BRUKER PHOTON 100 / Detector: CMOS / Date: Aug 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.34138 Å / Relative weight: 1
ReflectionResolution: 2.22→35.22 Å / Num. obs: 26472 / % possible obs: 99.9 % / Redundancy: 8.4 % / Rmerge(I) obs: 0.0771 / Net I/σ(I): 13.23
Reflection shellResolution: 2.22→2.25 Å / Rmerge(I) obs: 0.4425 / Mean I/σ(I) obs: 2.25 / Num. unique obs: 990 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
SADABSdata scaling
PDB_EXTRACT3.27data extraction
SAINTdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5DI7

5di7


Resolution: 2.22→35.22 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.922 / SU B: 8.044 / SU ML: 0.191 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.281 / ESU R Free: 0.227 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2514 1322 5 %RANDOM
Rwork0.1882 ---
obs0.1913 25034 99.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 237.98 Å2 / Biso mean: 45.948 Å2 / Biso min: 20.12 Å2
Baniso -1Baniso -2Baniso -3
1--0.45 Å2-0 Å20 Å2
2--2.79 Å20 Å2
3----2.34 Å2
Refinement stepCycle: final / Resolution: 2.22→35.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3746 0 51 166 3963
Biso mean--102.58 45.51 -
Num. residues----472
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0133880
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173760
X-RAY DIFFRACTIONr_angle_refined_deg1.7791.6375240
X-RAY DIFFRACTIONr_angle_other_deg1.3651.5788696
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7595466
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.39322.065184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.21115725
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.2311523
X-RAY DIFFRACTIONr_chiral_restr0.1760.2499
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024149
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02766
LS refinement shellResolution: 2.22→2.278 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 106 -
Rwork0.285 1776 -
all-1882 -
obs--97.66 %

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