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- PDB-5fqr: Selective estrogen receptor downregulator antagonists: Tetrahydro... -

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Basic information

Entry
Database: PDB / ID: 5fqr
TitleSelective estrogen receptor downregulator antagonists: Tetrahydroisoquinoline phenols 2.
ComponentsESTROGEN RECEPTOR
KeywordsSIGNALING PROTEIN / BREAST CANCER / ESTROGEN RECEPTOR DOWNREGULATOR / FULVESTRANT / THIQ / 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 / 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 / prostate epithelial cord elongation / epithelial cell development / negative regulation of smooth muscle cell apoptotic process / mammary gland branching involved in pregnancy / uterus development / vagina development / androgen metabolic process / TFIIB-class transcription factor binding / steroid hormone mediated signaling pathway / mammary gland alveolus development / intracellular estrogen receptor signaling pathway / cellular response to estrogen stimulus / estrogen response element binding / positive regulation of phospholipase C activity / intracellular steroid hormone receptor signaling pathway / negative regulation of canonical NF-kappaB signal transduction / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / protein localization to chromatin / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / steroid binding / nitric-oxide synthase regulator activity / ESR-mediated signaling / 14-3-3 protein binding / transcription corepressor binding / negative regulation of miRNA transcription / cellular response to estradiol stimulus / transcription coregulator binding / stem cell differentiation / nuclear estrogen receptor binding / positive regulation of nitric-oxide synthase activity / euchromatin / SUMOylation of intracellular receptors / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / Regulation of RUNX2 expression and activity / nuclear receptor activity / positive regulation of nitric oxide biosynthetic process / positive regulation of DNA-binding transcription factor activity / positive regulation of fibroblast proliferation / Ovarian tumor domain proteases / sequence-specific double-stranded DNA binding / response to estradiol / PIP3 activates AKT signaling / phospholipase C-activating G protein-coupled receptor signaling pathway / ATPase binding / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / regulation of inflammatory response / 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 / chromatin / regulation of DNA-templated transcription / 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 / membrane / identical protein binding / 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 / Nuclear hormones receptors DNA-binding region signature. ...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-QHG / Estrogen receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.88 Å
AuthorsScott, J.S. / Bailey, A. / Davies, R.D.M. / Degorce, S.L. / MacFaul, P.A. / Gingell, H. / Moss, T. / Norman, R.A. / Pink, J.H. / Rabow, A.A. ...Scott, J.S. / Bailey, A. / Davies, R.D.M. / Degorce, S.L. / MacFaul, P.A. / Gingell, H. / Moss, T. / Norman, R.A. / Pink, J.H. / Rabow, A.A. / Roberts, B. / Smith, P.D.
Citation
Journal: Acs Med.Chem.Lett. / Year: 2016
Title: Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat.
Authors: Scott, J.S. / Bailey, A. / Davies, R.D. / Degorce, S.L. / MacFaul, P.A. / Gingell, H. / Moss, T. / Norman, R.A. / Pink, J.H. / Rabow, A.A. / Roberts, B. / Smith, P.D.
#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
DepositionDec 14, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 10, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2016Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: audit_author / chem_comp_atom ...audit_author / chem_comp_atom / chem_comp_bond / citation_author / database_2 / pdbx_database_status / struct_site
Item: _audit_author.name / _citation_author.name ..._audit_author.name / _citation_author.name / _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)28,5932
Polymers28,2421
Non-polymers3511
Water1,58588
1
A: ESTROGEN RECEPTOR
hetero molecules

A: ESTROGEN RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1874
Polymers56,4842
Non-polymers7032
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation11_555-x+y,y,-z+1/21
Buried area2910 Å2
ΔGint-13.4 kcal/mol
Surface area19420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.100, 58.100, 274.380
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-2021-

HOH

21A-2083-

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-QHG / (E)-3-[4-[(1R)-6-HYDROXY-2-ISOBUTYL-3,4-DIHYDRO-1H-ISOQUINOLIN-1-YL]PHENYL]PROP-2-ENOIC ACID


Mass: 351.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25NO3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 88 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.07 Å3/Da / Density % sol: 40.5 % / Description: NONE
Crystal growDetails: 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 / Type: DIAMOND / Wavelength: 1
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 22344 / % possible obs: 99.8 % / Observed criterion σ(I): 2 / Redundancy: 9 % / Rmerge(I) obs: 0.05

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Processing

SoftwareName: REFMAC / Version: 5.7.0032 / Classification: refinement
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.88→50.32 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.929 / SU B: 5.815 / SU ML: 0.088 / Cross valid method: THROUGHOUT / ESU R: 0.149 / ESU R Free: 0.134 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23686 1180 5 %RANDOM
Rwork0.21286 ---
obs0.21402 22344 99.88 %-
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 mean: 30.215 Å2
Baniso -1Baniso -2Baniso -3
1-0.3 Å20.3 Å20 Å2
2--0.3 Å20 Å2
3----0.96 Å2
Refinement stepCycle: LAST / Resolution: 1.88→50.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1807 0 26 88 1921
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0191901
X-RAY DIFFRACTIONr_bond_other_d0.0010.021836
X-RAY DIFFRACTIONr_angle_refined_deg0.9281.992578
X-RAY DIFFRACTIONr_angle_other_deg0.70434214
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.0735230
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.04524.2580
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.87315342
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.322159
X-RAY DIFFRACTIONr_chiral_restr0.0510.2301
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022120
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02417
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_it0.822.287923
X-RAY DIFFRACTIONr_mcbond_other0.8182.287922
X-RAY DIFFRACTIONr_mcangle_it1.3593.4151152
X-RAY DIFFRACTIONr_mcangle_other1.3593.4151153
X-RAY DIFFRACTIONr_scbond_it1.0732.443978
X-RAY DIFFRACTIONr_scbond_other1.0512.449948
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.7263.6181387
X-RAY DIFFRACTIONr_long_range_B_refined3.95618.8092238
X-RAY DIFFRACTIONr_long_range_B_other3.71518.4972159
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
Rfree0.31 85 -
Rwork0.238 1595 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 12.5805 Å / Origin y: 34.1681 Å / Origin z: 69.0594 Å
111213212223313233
T0.0089 Å2-0.0155 Å20.0041 Å2-0.042 Å2-0.0015 Å2--0.0305 Å2
L0.9377 °2-0.6936 °2-0.3053 °2-0.7789 °20.2509 °2--0.9503 °2
S-0.0101 Å °-0.0176 Å °0.0757 Å °-0.0124 Å °0.0138 Å °-0.0504 Å °-0.0309 Å °0.1351 Å °-0.0037 Å °

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