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- PDB-5acc: A Novel Oral Selective Estrogen Receptor Down-regulator, AZD9496,... -

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Basic information

Entry
Database: PDB / ID: 5acc
TitleA Novel Oral Selective Estrogen Receptor Down-regulator, AZD9496, drives Tumour Growth Inhibition in Estrogen Receptor positive and ESR1 Mutant Models
ComponentsESTROGEN RECEPTOR
KeywordsSIGNALING PROTEIN / SERD / METASTATIC BREAST CANCER / ER MUTATION / ESR1 MUTATION / COMBINATION THERAPY
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / 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 / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / epithelial cell proliferation involved in mammary gland duct elongation ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / 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 / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / epithelial cell development / negative regulation of smooth muscle cell apoptotic process / uterus development / mammary gland branching involved in pregnancy / vagina development / TFIIB-class transcription factor binding / steroid hormone receptor signaling pathway / androgen metabolic process / cellular response to estrogen stimulus / mammary gland alveolus development / estrogen response element binding / Mitochondrial unfolded protein response (UPRmt) / nuclear receptor-mediated steroid hormone signaling pathway / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / protein localization to chromatin / estrogen receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / steroid binding / 14-3-3 protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / TBP-class protein binding / nitric-oxide synthase regulator activity / positive regulation of nitric-oxide synthase activity / negative regulation of miRNA transcription / ESR-mediated signaling / positive regulation of DNA-binding transcription factor activity / transcription coregulator binding / transcription corepressor binding / nuclear estrogen receptor binding / negative regulation of DNA-binding transcription factor activity / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / transcription coactivator binding / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / nuclear receptor activity / positive regulation of fibroblast proliferation / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / response to estradiol / PIP3 activates AKT signaling / ATPase binding / positive regulation of cytosolic calcium ion concentration / DNA-binding transcription activator activity, RNA polymerase II-specific / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of inflammatory response / 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 / Extra-nuclear estrogen signaling / calmodulin binding / chromatin remodeling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / 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 / 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 / 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
Chem-KE9 / Estrogen receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsNorman, R.A. / Weir, H.M. / Bradbury, R.H. / Lawson, M. / Rabow, A.A. / Buttar, D. / Callis, R.J. / Curwen, J.O. / de Almeida, C. / Ballard, P. ...Norman, R.A. / Weir, H.M. / Bradbury, R.H. / Lawson, M. / Rabow, A.A. / Buttar, D. / Callis, R.J. / Curwen, J.O. / de Almeida, C. / Ballard, P. / Hulse, M. / Donald, C.S. / Feron, L.J.L. / Gingell, H. / Karoutchi, G. / MacFaul, P. / Moss, T. / Pearson, S.E. / Tonge, M. / Davies, G. / Walker, G.E. / Wilson, Z. / Rowlinson, R. / Powell, S. / Hemsley, P. / Linney, E. / Campbell, H. / Ghazoui, Z. / Sadler, C. / Richmond, G. / Pazolli, E. / Mazzola, A.M. / DCruz, C. / De Savi, C.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-Fluoro-2-Methylpropyl)-3-Methyl-2, 3,4,9-Tetrahydro-1H-Pyrido[3,4-B]Indol-1-Yl)Phenyl)Acrylic Acid (Azd9496), a ...Title: Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-Fluoro-2-Methylpropyl)-3-Methyl-2, 3,4,9-Tetrahydro-1H-Pyrido[3,4-B]Indol-1-Yl)Phenyl)Acrylic Acid (Azd9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
Authors: De Savi, C. / Bradbury, R.H. / Rabow, A.A. / Norman, R.A. / De Almeida, C. / Andrews, D.M. / Ballard, P. / Buttar, D. / Callis, R.J. / Currie, G.S. / Curwen, J.O. / Davies, C.D. / Donald, C. ...Authors: De Savi, C. / Bradbury, R.H. / Rabow, A.A. / Norman, R.A. / De Almeida, C. / Andrews, D.M. / Ballard, P. / Buttar, D. / Callis, R.J. / Currie, G.S. / Curwen, J.O. / Davies, C.D. / Donald, C.S. / Feron, L.J.L. / Gingell, H. / Glossop, S.C. / Hayter, B.R. / Hussain, S. / Karoutchi, G. / Lamont, S.G. / Macfaul, P. / Moss, T.A. / Pearson, S.E. / Tonge, M. / Walker, G.E. / Weir, H.M. / Wilson, Z.
History
DepositionAug 15, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 16, 2015Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,6852
Polymers28,2421
Non-polymers4421
Water1,42379
1
A: ESTROGEN RECEPTOR
hetero molecules

A: ESTROGEN RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,3694
Polymers56,4842
Non-polymers8852
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation11_555-x+y,y,-z+1/21
Buried area3000 Å2
ΔGint-12.8 kcal/mol
Surface area19180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.860, 57.860, 274.040
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-2017-

HOH

21A-2075-

HOH

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Components

#1: Protein ESTROGEN RECEPTOR / ER / ER-ALPHA / ESTRADIOL RECEPTOR / NUCLEAR RECEPTOR SUBFAMILY 3 GROUP A MEMBER 1 / ESTROGEN RECEPTOR ALPHA


Mass: 28242.049 Da / Num. of mol.: 1 / Fragment: LIGAND-BINDING DOMAIN, UNP RESIDUES 307-554 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): GOLD / References: UniProt: P03372
#2: Chemical ChemComp-KE9 / (E)-3-(3,5-DIFLUORO-4-((1R,3R)-2-(2-FLUORO-2- METHYLPROPYL)-3-METHYL-2,3,4,9-TETRAHYDRO-1H-PYRIDO(3,4-B)INDOL-1-YL)PHENYL)ACRYLIC ACID


Mass: 442.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25F3N2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.45 Å3/Da / Density % sol: 49.87 % / Description: NONE
Crystal growpH: 6.5
Details: 0.1 M PCTP, PH 6.5 (0.04 M SODIUM PROPIONATE, 0.02 M SODIUM CACODYLATE, 0.04 M BIS-TRIS PROPANE), 22% PEG3350, 0.2M MGCL2

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.96
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96 Å / Relative weight: 1
ReflectionResolution: 1.8→54.81 Å / Num. obs: 26271 / % possible obs: 99.1 % / Observed criterion σ(I): 2 / Redundancy: 6.9 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 13.4
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 2.8 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IN-HOUSE MODEL

Resolution: 1.88→50.11 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.925 / SU B: 8.311 / SU ML: 0.11 / Cross valid method: THROUGHOUT / ESU R: 0.152 / ESU R Free: 0.151 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.26628 1161 5 %RANDOM
Rwork0.21685 ---
obs0.21915 21896 98.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.43 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å2-0.06 Å20 Å2
2---0.12 Å20 Å2
3---0.38 Å2
Refinement stepCycle: LAST / Resolution: 1.88→50.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1800 0 32 79 1911
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0191868
X-RAY DIFFRACTIONr_bond_other_d0.0020.021806
X-RAY DIFFRACTIONr_angle_refined_deg1.3292.0022534
X-RAY DIFFRACTIONr_angle_other_deg0.9334141
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0155224
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.17824.21176
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.11815334
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.793159
X-RAY DIFFRACTIONr_chiral_restr0.0740.2297
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022067
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02402
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_it0.7372.128908
X-RAY DIFFRACTIONr_mcbond_other0.732.128907
X-RAY DIFFRACTIONr_mcangle_it1.1643.1811128
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.042.266960
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: 1.88→1.929 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.32 83 -
Rwork0.265 1590 -
obs--98.64 %
Refinement TLS params.Method: refined / Origin x: 12.559 Å / Origin y: 33.9858 Å / Origin z: 68.9596 Å
111213212223313233
T0.0168 Å2-0.0344 Å2-0.0116 Å2-0.1104 Å20.0084 Å2--0.0807 Å2
L1.4429 °2-0.7811 °2-0.4057 °2-1.485 °20.7531 °2--3.2415 °2
S-0.0596 Å °-0.0373 Å °0.0314 Å °0.0291 Å °0.0469 Å °-0.125 Å °-0.0783 Å °0.4441 Å °0.0127 Å °

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