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- PDB-5aau: Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4... -

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Entry
Database: PDB / ID: 5aau
TitleOptimization of a novel binding motif to 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
ComponentsESTROGEN RECEPTOR
KeywordsSIGNALING PROTEIN / BREAST CANCER / ESTROGEN RECEPTOR DOWNREGULATOR / FULVESTRANT / AZD9496 / NUCLEAR HORMONE RECEPTOR
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 / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / vagina development / TFIIB-class transcription factor binding / steroid hormone receptor signaling pathway / 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 / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / negative regulation of canonical NF-kappaB signal transduction / 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 / TBP-class protein binding / nitric-oxide synthase regulator activity / negative regulation of miRNA transcription / positive regulation of nitric-oxide synthase activity / ESR-mediated signaling / transcription coregulator binding / transcription corepressor binding / nuclear estrogen receptor binding / positive regulation of DNA-binding transcription factor activity / stem cell differentiation / cellular response to estradiol stimulus / SUMOylation of intracellular receptors / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / nuclear receptor activity / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of fibroblast proliferation / male gonad development / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cytosolic calcium ion concentration / DNA-binding transcription activator activity, RNA polymerase II-specific / regulation of inflammatory response / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / transcription regulator complex / Estrogen-dependent gene expression / Extra-nuclear estrogen signaling / DNA-binding transcription factor activity, RNA polymerase II-specific / 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 / Golgi apparatus / negative regulation of transcription by RNA polymerase II / 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-XBR / Estrogen receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsNorman, R.A. / Bradbury, R.H. / de Almeida, C. / Andrews, D.M. / Ballard, P. / Buttar, D. / Callis, R.J. / Currie, G.S. / Curwen, J.O. / Davies, C.D. ...Norman, R.A. / Bradbury, R.H. / de Almeida, C. / Andrews, D.M. / Ballard, P. / Buttar, D. / Callis, R.J. / Currie, G.S. / Curwen, J.O. / Davies, C.D. / de Savi, C. / Donald, C.S. / Feron, L.J.L. / Glossop, S.C. / Hayter, B.R. / Karoutchi, G. / Lamont, S.G. / MacFaul, P. / Moss, T. / Pearson, S.E. / Rabow, A.A. / Tonge, M. / Walker, G.E. / Weir, H.M. / Wilson, Z.
Citation
Journal: 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. / Currie, G.S. / Davies, C. / Donald, C. / Feron, L. / ...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. / Currie, G.S. / Davies, C. / Donald, C. / Feron, L. / Hayter, B.R. / Hussain, S. / Karoutchi, G. / Lamont, S. / Macfaul, P.A. / Moss, T.A. / Pearson, S. / Tonge, M. / Walker, G. / Weir, H. / Wilson, Z.
#1: Journal: Cancer Res. / Year: 2016
Title: Azd9496: An Oral Estrogen Receptor Inhibitor that Blocks the Growth of Er-Positive and Esr1-Mutant Breast Tumors in Preclinical Models.
Authors: 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. / Karoutchi, G. / ...Authors: 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. / Karoutchi, G. / Macfaul, P. / Moss, T. / Norman, R.A. / Pearson, S.E. / Tonge, M. / Davies, G. / Walker, G.E. / Wilson, Z. / Rowlinson, R. / Powell, S. / Sadler, C. / Richmond, G. / Ladd, B. / Pazolli, E. / Mazzola, A.M. / D'Cruz, C. / De Savi, C.
History
DepositionJul 28, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 14, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2015Group: Database references
Revision 1.2Oct 12, 2016Group: Database references
Revision 1.3May 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
B: ESTROGEN RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,0534
Polymers57,3432
Non-polymers7102
Water4,089227
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2970 Å2
ΔGint-13.1 kcal/mol
Surface area18880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.407, 51.396, 85.181
Angle α, β, γ (deg.)90.00, 93.66, 90.00
Int Tables number5
Space group name H-MC121

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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: 28671.584 Da / Num. of mol.: 2 / 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-XBR / 3-(1-(4-Chlorophenyl)-3,4-dihydro-1H-pyrido(3,4-b)indol-2(9H)-yl)propanoic acid


Mass: 354.830 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H19ClN2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / 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: 2.07 Å3/Da / Density % sol: 40.5 % / 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: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.96
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96 Å / Relative weight: 1
ReflectionResolution: 1.9→85 Å / Num. obs: 31454 / % possible obs: 91 % / Observed criterion σ(I): 2 / Redundancy: 3.3 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 15.3
Reflection shellResolution: 1.9→2 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 1.8 / % possible all: 57.3

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Processing

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

Resolution: 1.9→25.7 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.938 / SU B: 9.516 / SU ML: 0.121 / Cross valid method: THROUGHOUT / ESU R: 0.171 / ESU R Free: 0.159 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.22591 1629 4.9 %RANDOM
Rwork0.17293 ---
obs0.17551 31453 90.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.396 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å2-0.02 Å2
2---0.51 Å20 Å2
3---0.33 Å2
Refinement stepCycle: LAST / Resolution: 1.9→25.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3532 0 50 227 3809
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0240.0193764
X-RAY DIFFRACTIONr_bond_other_d0.0020.023637
X-RAY DIFFRACTIONr_angle_refined_deg2.1041.9865122
X-RAY DIFFRACTIONr_angle_other_deg1.14938346
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9455474
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.29823.974156
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.45115670
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.9831519
X-RAY DIFFRACTIONr_chiral_restr0.1370.2600
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.024178
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02841
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_it1.8032.3591837
X-RAY DIFFRACTIONr_mcbond_other1.7912.3581836
X-RAY DIFFRACTIONr_mcangle_it2.7343.5062293
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.3892.6081927
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: 1.901→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.288 55 -
Rwork0.304 1279 -
obs--50.72 %
Refinement TLS params.Method: refined / Origin x: 8.2355 Å / Origin y: -0.1037 Å / Origin z: 22.8836 Å
111213212223313233
T0.0199 Å20.0181 Å20.0002 Å2-0.0258 Å20.0006 Å2--0.0085 Å2
L1.0167 °2-0.3181 °20.0497 °2-0.4551 °2-0.3365 °2--1.0224 °2
S0.0253 Å °-0.0452 Å °-0.0235 Å °-0.0132 Å °0.0465 Å °0.0157 Å °-0.0658 Å °-0.0883 Å °-0.0719 Å °

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