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- PDB-7msa: GDC-9545 in complex with estrogen receptor alpha -

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Basic information

Entry
Database: PDB / ID: 7msa
TitleGDC-9545 in complex with estrogen receptor alpha
ComponentsEstrogen receptor
KeywordsTRANSCRIPTION / antagonist / breast cancer
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-G9J / Chem-ZNM / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.24 Å
AuthorsKiefer, J.R. / Vinogradova, M. / Liang, J. / Zbieg, J.R. / Wang, X. / Ortwine, D.F.
CitationJournal: J.Med.Chem. / Year: 2021
Title: GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer.
Authors: Liang, J. / Zbieg, J.R. / Blake, R.A. / Chang, J.H. / Daly, S. / DiPasquale, A.G. / Friedman, L.S. / Gelzleichter, T. / Gill, M. / Giltnane, J.M. / Goodacre, S. / Guan, J. / Hartman, S.J. / ...Authors: Liang, J. / Zbieg, J.R. / Blake, R.A. / Chang, J.H. / Daly, S. / DiPasquale, A.G. / Friedman, L.S. / Gelzleichter, T. / Gill, M. / Giltnane, J.M. / Goodacre, S. / Guan, J. / Hartman, S.J. / Ingalla, E.R. / Kategaya, L. / Kiefer, J.R. / Kleinheinz, T. / Labadie, S.S. / Lai, T. / Li, J. / Liao, J. / Liu, Z. / Mody, V. / McLean, N. / Metcalfe, C. / Nannini, M.A. / Oeh, J. / O'Rourke, M.G. / Ortwine, D.F. / Ran, Y. / Ray, N.C. / Roussel, F. / Sambrone, A. / Sampath, D. / Schutt, L.K. / Vinogradova, M. / Wai, J. / Wang, T. / Wertz, I.E. / White, J.R. / Yeap, S.K. / Young, A. / Zhang, B. / Zheng, X. / Zhou, W. / Zhong, Y. / Wang, X.
History
DepositionMay 10, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 8, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)129,8798
Polymers127,9214
Non-polymers1,9584
Water1,62190
1
D: Estrogen receptor
A: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9394
Polymers63,9612
Non-polymers9792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2860 Å2
ΔGint-12 kcal/mol
Surface area19290 Å2
MethodPISA
2
C: Estrogen receptor
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9394
Polymers63,9612
Non-polymers9792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3030 Å2
ΔGint-15 kcal/mol
Surface area18510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.081, 58.937, 93.551
Angle α, β, γ (deg.)86.430, 75.080, 63.250
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: 31980.295 Da / Num. of mol.: 4
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-G9J / (2S)-3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-1-benzopyran-6-ol


Mass: 456.273 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H17IO3
#3: Chemical ChemComp-ZNM / 3-[(1R,3R)-1-(2,6-difluoro-4-{[1-(3-fluoropropyl)azetidin-3-yl]amino}phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol


Mass: 522.553 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H31F5N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 90 / 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: 1.97 Å3/Da / Density % sol: 37.57 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 6
Details: 35% PEG3350, 0.1M Bis-Tris, pH 6.0, 150 mM MgCl2, and 10 mM GDC-9545

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.89
11H, H-K, H-L20.11
ReflectionResolution: 2.23→90.22 Å / Num. obs: 42070 / % possible obs: 88.5 % / Redundancy: 3.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.052 / Rpim(I) all: 0.031 / Rrim(I) all: 0.061 / Net I/σ(I): 12.2 / Num. measured all: 159976
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.23-2.353.90.5062409562260.8850.2960.5872.489.5
7.05-90.223.80.033493113110.9980.020.0392986.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
Aimless0.2.8data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.24→33.22 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.931 / SU B: 12.576 / SU ML: 0.166 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.081 / ESU R Free: 0.053 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2464 2118 5.1 %RANDOM
Rwork0.194 ---
obs0.1968 39433 81.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 145.62 Å2 / Biso mean: 69.223 Å2 / Biso min: 33.29 Å2
Baniso -1Baniso -2Baniso -3
1--8.27 Å2-2.95 Å2-3.25 Å2
2---19.52 Å22.97 Å2
3---27.79 Å2
Refinement stepCycle: final / Resolution: 2.24→33.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6984 0 126 93 7203
Biso mean--70.73 64.84 -
Num. residues----912
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0137252
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176829
X-RAY DIFFRACTIONr_angle_refined_deg1.4251.6319836
X-RAY DIFFRACTIONr_angle_other_deg1.2481.57815743
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3565899
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.84622.689305
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.741151255
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7031533
X-RAY DIFFRACTIONr_chiral_restr0.0670.2967
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.028058
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021383
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)
12.8693-0.84530.75165.4664-0.74133.9226-0.11250.06360.3193-0.0125-0.0094-0.0269-0.32070.17060.12190.1542-0.08570.03220.0509-0.02830.0855-49.50526.2778-50.8089
23.67440.48230.87123.98230.17714.0202-0.01710.0108-0.00830.0362-0.02990.58250.3187-0.3690.04690.2084-0.06720.0990.0434-0.02620.1321-60.4499-16.4864-50.8865
33.2077-0.2126-0.22834.8945-0.10294.4622-0.0169-0.0910.0411-0.0079-0.04210.163-0.2731-0.28510.0590.18950.06580.05040.03520.00790.0247-60.64221.8762-96.5013
42.71130.1263-0.49735.914-0.92263.25830.0231-0.0446-0.2536-0.0556-0.0329-0.26980.24010.1830.00980.16770.08090.06130.0721-0.01830.1484-49.2187-0.2217-95.7991
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1D306 - 545
2X-RAY DIFFRACTION2A306 - 545
3X-RAY DIFFRACTION3C306 - 544
4X-RAY DIFFRACTION4B306 - 545

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