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- PDB-5aav: Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4... -
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Basic information
Entry | Database: PDB / ID: 5aav | ||||||
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Title | Optimization 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 | ||||||
![]() | (ESTROGEN RECEPTOR) x 2 | ||||||
![]() | SIGNALING PROTEIN / BREAST CANCER / ESTROGEN RECEPTOR DOWNREGULATOR / FULVESTRANT / AZD9496 / NUCLEAR HORMONE RECEPTOR | ||||||
Function / homology | ![]() 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 / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / nuclear estrogen receptor activity / 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 / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / nuclear estrogen receptor activity / epithelial cell proliferation involved in mammary gland duct elongation / epithelial cell development / prostate epithelial cord elongation / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / TFIIB-class transcription factor binding / androgen metabolic process / steroid hormone receptor signaling pathway / mammary gland alveolus development / estrogen receptor signaling pathway / 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 / protein localization to chromatin / 14-3-3 protein binding / TBP-class protein binding / nitric-oxide synthase regulator activity / steroid 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 / SUMOylation of intracellular receptors / euchromatin / negative regulation of DNA-binding transcription factor activity / beta-catenin binding / transcription coactivator binding / positive regulation of DNA-binding transcription factor activity / Nuclear Receptor transcription pathway / response to estrogen / Regulation of RUNX2 expression and activity / Constitutive Signaling by Aberrant PI3K in Cancer / nuclear receptor activity / male gonad development / positive regulation of nitric oxide biosynthetic process / sequence-specific double-stranded DNA binding / positive regulation of fibroblast proliferation / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / ATPase binding / regulation of inflammatory response / fibroblast proliferation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / 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 / 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 / chromatin / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of DNA-templated transcription / Golgi apparatus / enzyme binding / 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 / membrane / nucleus / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | 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. ...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. | ||||||
![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 147.2 KB | Display | ![]() |
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PDB format | ![]() | 115.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 977.2 KB | Display | ![]() |
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Full document | ![]() | 981.2 KB | Display | |
Data in XML | ![]() | 19.5 KB | Display | |
Data in CIF | ![]() | 27.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
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Links
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Assembly
Deposited unit | ![]()
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Unit cell |
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Components
#1: Protein | Mass: 28655.521 Da / Num. of mol.: 1 / Fragment: LIGAND-BINDING DOMAIN / Mutation: YES Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() | ||
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#2: Protein | Mass: 28637.482 Da / Num. of mol.: 1 / Fragment: LIGAND-BINDING DOMAIN / Mutation: YES Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() | ||
#3: Chemical | #4: Water | ChemComp-HOH / | |
-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.02 Å3/Da / Density % sol: 39.22 % / Description: NONE |
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Crystal grow | pH: 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 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.96 Å / Relative weight: 1 |
Reflection | Resolution: 1.95→52.7 Å / Num. obs: 30991 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 6.4 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 16.3 |
Reflection shell | Resolution: 1.95→2.06 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 4.7 / % possible all: 99.9 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: IN HOUSE MODEL Resolution: 1.95→44.32 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.919 / SU B: 8.947 / SU ML: 0.115 / Cross valid method: THROUGHOUT / ESU R: 0.185 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 28.491 Å2
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Refinement step | Cycle: LAST / Resolution: 1.95→44.32 Å
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Refine LS restraints |
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