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- PDB-6pfm: Crystal structure of GDC-0927 bound to estrogen receptor alpha -

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Basic information

Entry
Database: PDB / ID: 6pfm
TitleCrystal structure of GDC-0927 bound to estrogen receptor alpha
ComponentsEstrogen receptor
KeywordsNUCLEAR PROTEIN / antagonist / breast cancer / ligand
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 / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor ...Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor/oestrogen-related receptor / : / Retinoid X Receptor / Retinoid X 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-OGJ / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.84 Å
AuthorsKiefer, J.R. / Vinogradova, M. / Liang, J. / Zhang, B. / Wang, X. / Zbieg, J.R. / Labadie, S.S. / Li, J. / Ray, N.C. / Ortwine, D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927.
Authors: Labadie, S.S. / Li, J. / Blake, R.A. / Chang, J.H. / Goodacre, S. / Hartman, S.J. / Liang, W. / Kiefer, J.R. / Kleinheinz, T. / Lai, T. / Liao, J. / Ortwine, D.F. / Mody, V. / Ray, N.C. / ...Authors: Labadie, S.S. / Li, J. / Blake, R.A. / Chang, J.H. / Goodacre, S. / Hartman, S.J. / Liang, W. / Kiefer, J.R. / Kleinheinz, T. / Lai, T. / Liao, J. / Ortwine, D.F. / Mody, V. / Ray, N.C. / Roussel, F. / Vinogradova, M. / Yeap, S.K. / Zhang, B. / Zheng, X. / Zbieg, J.R. / Liang, J. / Wang, X.
History
DepositionJun 21, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 17, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 31, 2019Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Aug 28, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)64,8844
Polymers63,9612
Non-polymers9232
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2820 Å2
ΔGint-14 kcal/mol
Surface area20980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.106, 144.106, 171.064
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11D-704-

HOH

21A-703-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11D
21A

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: _ / Auth seq-ID: 307 - 529 / Label seq-ID: 34 - 256

Dom-IDAuth asym-IDLabel asym-ID
1DA
2AB

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Components

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


Mass: 31980.295 Da / Num. of mol.: 2 / 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 (E. coli) / References: UniProt: P03372
#2: Chemical ChemComp-OGJ / (2S)-2-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-1-benzopyran-6-ol


Mass: 461.525 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H28FNO4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / 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: 2.67 Å3/Da / Density % sol: 53.97 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: 25-35% PEG 3,350 0.1 M Bis-Tris (pH 6.1-6.5) 150-300 mM MgCl2

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Mar 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.84→35 Å / Num. obs: 16277 / % possible obs: 100 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.131 / Rpim(I) all: 0.055 / Rrim(I) all: 0.142 / Χ2: 0.952 / Net I/σ(I): 6.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.84-2.95.20.97980.4580.4270.9990.55399.9
2.9-2.955.60.8598100.580.3920.9460.63699.9
2.95-3.015.90.6998050.8670.3110.7670.62399.9
3.01-3.0760.6878110.7940.3030.7530.638100
3.07-3.146.10.6467840.8280.2830.7070.659100
3.14-3.216.20.5648110.8320.2440.6150.66699.9
3.21-3.296.30.4878050.9170.210.5310.709100
3.29-3.386.40.3938140.940.1670.4270.748100
3.38-3.486.40.3527880.9220.1490.3830.829100
3.48-3.596.60.2868090.9610.1190.3110.844100
3.59-3.726.80.2258180.9750.0920.2430.955100
3.72-3.876.90.1788130.9880.0720.1920.962100
3.87-4.0470.1398090.9920.0560.151.079100
4.04-4.267.10.1178090.9940.0460.1261.118100
4.26-4.527.20.0938150.9960.0370.11.079100
4.52-4.877.40.0818330.9960.0320.0871.189100
4.87-5.367.30.0818040.9970.0320.0871.174100
5.36-6.137.20.0958270.9950.0370.1021.28199.9
6.13-7.717.20.0628370.9990.0250.0671.217100

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
SCALEPACKdata scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.84→33.95 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.907 / SU B: 36.727 / SU ML: 0.317 / SU R Cruickshank DPI: 1.4479 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.448 / ESU R Free: 0.352
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2488 814 5 %RANDOM
Rwork0.2092 ---
obs0.2111 15463 99.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 160.22 Å2 / Biso mean: 73.166 Å2 / Biso min: 1.63 Å2
Baniso -1Baniso -2Baniso -3
1-0.86 Å20.43 Å20 Å2
2--0.86 Å20 Å2
3----2.8 Å2
Refinement stepCycle: final / Resolution: 2.84→33.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3594 0 120 22 3736
Biso mean--77.16 54.52 -
Num. residues----459
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0133759
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173562
X-RAY DIFFRACTIONr_angle_refined_deg1.3571.6515093
X-RAY DIFFRACTIONr_angle_other_deg1.1941.5878257
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9955460
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.27923.152165
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.47815680
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5981516
X-RAY DIFFRACTIONr_chiral_restr0.0590.2489
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024064
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02724
Refine LS restraints NCS

Ens-ID: 1 / Number: 6714 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.11 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1D
2A
LS refinement shellResolution: 2.841→2.914 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 59 -
Rwork0.346 1088 -
all-1147 -
obs--97.78 %
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)
12.0388-0.6911-0.43034.81071.15863.0151-0.0119-0.0846-0.24840.14070.0557-0.40240.28450.1534-0.04380.21230.0461-0.05160.26370.02630.093118.963964.18344.8573
22.5452-1.44210.03786.3203-0.99791.7998-0.3142-0.3901-0.11650.80320.446-0.56430.21810.0908-0.13180.53930.0997-0.25180.5076-0.04650.172527.180366.123669.2282
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1D307 - 545
2X-RAY DIFFRACTION2A307 - 530

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