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- PDB-7rs0: Crystal Structure of the ER-alpha Ligand-binding Domain (L372S, L... -

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Basic information

Entry
Database: PDB / ID: 7rs0
TitleCrystal Structure of the ER-alpha Ligand-binding Domain (L372S, L536S) in complex with DMERI-18
ComponentsEstrogen receptor
KeywordsTRANSCRIPTION/TRANSCRIPTION INHIBITOR / ER-alpha / ligand complex / DMERI / TRANSCRIPTION-TRANSCRIPTION INHIBITOR complex
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / 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 ...regulation of epithelial cell apoptotic process / 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 / mammary gland branching involved in pregnancy / uterus development / negative regulation of smooth muscle cell apoptotic process / vagina development / TFIIB-class transcription factor binding / androgen 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 / positive regulation of nitric-oxide synthase activity / estrogen receptor signaling pathway / protein localization to chromatin / steroid binding / 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 / ESR-mediated signaling / negative regulation of miRNA transcription / TBP-class protein binding / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / transcription corepressor binding / transcription coregulator binding / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / 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 / 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 / DNA-binding transcription factor activity, RNA polymerase II-specific / calmodulin binding / Extra-nuclear estrogen signaling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin remodeling / DNA-binding transcription factor activity / negative regulation of gene expression / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / protein kinase binding / chromatin / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / Golgi apparatus / signal transduction / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding / nucleus / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
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 hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type ...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 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
Similarity search - Domain/homology
Chem-7I9 / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.67 Å
AuthorsMin, J. / Nwachukwu, J.C. / Min, C.K. / Njeri, J.W. / Srinivasan, S. / Rangarajan, E.S. / Nettles, C.C. / Yan, S. / Houtman, R. / Griffin, P.R. ...Min, J. / Nwachukwu, J.C. / Min, C.K. / Njeri, J.W. / Srinivasan, S. / Rangarajan, E.S. / Nettles, C.C. / Yan, S. / Houtman, R. / Griffin, P.R. / Izard, T. / Katzenellenbogen, B.S. / Katzenellenbogen, J.A. / Nettles, K.W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2021
Title: Dual-mechanism estrogen receptor inhibitors.
Authors: Min, J. / Nwachukwu, J.C. / Min, C.K. / Njeri, J.W. / Srinivasan, S. / Rangarajan, E.S. / Nettles, C.C. / Sanabria Guillen, V. / Ziegler, Y. / Yan, S. / Carlson, K.E. / Hou, Y. / Kim, S.H. / ...Authors: Min, J. / Nwachukwu, J.C. / Min, C.K. / Njeri, J.W. / Srinivasan, S. / Rangarajan, E.S. / Nettles, C.C. / Sanabria Guillen, V. / Ziegler, Y. / Yan, S. / Carlson, K.E. / Hou, Y. / Kim, S.H. / Novick, S. / Pascal, B.D. / Houtman, R. / Griffin, P.R. / Izard, T. / Katzenellenbogen, B.S. / Katzenellenbogen, J.A. / Nettles, K.W.
History
DepositionAug 10, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 15, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 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

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Assembly

Deposited unit
A: Estrogen receptor
B: Estrogen receptor
C: Estrogen receptor
D: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,2698
Polymers117,5224
Non-polymers2,7474
Water5,549308
1
A: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,1354
Polymers58,7612
Non-polymers1,3742
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3060 Å2
ΔGint-13 kcal/mol
Surface area19080 Å2
MethodPISA
2
C: Estrogen receptor
D: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,1354
Polymers58,7612
Non-polymers1,3742
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3180 Å2
ΔGint-13 kcal/mol
Surface area18320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.270, 58.804, 92.667
Angle α, β, γ (deg.)79.950, 75.460, 63.100
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 29380.520 Da / Num. of mol.: 4 / Fragment: Ligand binding domain / Mutation: L372S, L536S
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: Chemical
ChemComp-7I9 / (1R,2S,4R,5R,6R)-5-(4-hydroxyphenyl)-N-(4-methoxyphenyl)-6-(4-propoxyphenyl)-N-(2,2,2-trifluoroethyl)-7-oxabicyclo[2.2.1]heptane-2-sulfonamide


Mass: 686.781 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C36H41F3N2O6S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / Source method: isolated from a natural source / Formula: H2O
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: 2.13 Å3/Da / Density % sol: 42.17 %
Crystal growTemperature: 298 K / Method: evaporation
Details: 20-25% PEG 3350, 200 mM MgCl2, 0.1 M Bis-Tris/Hepes/Tris-HCl
PH range: 6.5 - 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Mar 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.67→89.48 Å / Num. obs: 63812 / % possible obs: 89.7 % / Redundancy: 7.8 % / CC1/2: 0.998 / Net I/σ(I): 13.6
Reflection shellResolution: 1.7→1.89 Å / Num. unique obs: 3191 / CC1/2: 0.528

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHASERphasing
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
AutoProcessdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdbid 2QXS

2qxs


Resolution: 1.67→89.48 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.935 / SU B: 7.635 / SU ML: 0.115 / Cross valid method: THROUGHOUT / ESU R: 0.2 / ESU R Free: 0.166 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2269 3158 4.9 %RANDOM
Rwork0.1923 ---
obs0.1941 60676 57.1 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 181.89 Å2 / Biso mean: 42.014 Å2 / Biso min: 12.46 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å2-0.01 Å2-0.09 Å2
2--0.39 Å2-0.05 Å2
3----0.53 Å2
Refinement stepCycle: final / Resolution: 1.67→89.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7242 0 121 308 7671
Biso mean--67.44 39.89 -
Num. residues----909
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0187521
X-RAY DIFFRACTIONr_bond_other_d0.0010.027204
X-RAY DIFFRACTIONr_angle_refined_deg1.2381.93510183
X-RAY DIFFRACTIONr_angle_other_deg1.0952.93416692
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1615901
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.3124.332307
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.096151400
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7591538
X-RAY DIFFRACTIONr_chiral_restr0.0750.21194
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.028007
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021411
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_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.673→1.717 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 1 -
Rwork0.428 50 -
all-51 -
obs--0.62 %
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)
11.8772-0.1746-0.22144.25220.98652.3866-0.03290.0623-0.2162-0.0271-0.00510.12960.1752-0.13940.0380.026-0.0274-0.00150.04810.02760.0839-8.302-1.31323.086
22.18220.2570.10313.1407-0.41822.78660.00690.0640.0514-0.07720.0462-0.1363-0.25980.1825-0.05310.0616-0.02360.01780.0163-0.00970.02593.13220.64325.462
31.81740.68370.24263.43830.76121.9217-0.0855-0.08080.19870.1631-0.01940.0727-0.0586-0.0610.1050.02090.0087-0.00860.0140.00790.083114.80910.38568.922
42.5494-0.44580.37233.1385-0.26981.7345-0.0452-0.01130.0486-0.0152-0.024-0.44250.18170.17910.06910.06320.0180.04480.01970.0050.107726.265-11.88766.769
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A305 - 546
2X-RAY DIFFRACTION2B305 - 546
3X-RAY DIFFRACTION3C305 - 546
4X-RAY DIFFRACTION4D305 - 546

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