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- PDB-6iar: Tricyclic indazoles a novel class of selective estrogen receptor ... -

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Basic information

Entry
Database: PDB / ID: 6iar
TitleTricyclic indazoles a novel class of selective estrogen receptor degrader antagonists
ComponentsEstrogen receptor
KeywordsDNA BINDING PROTEIN / Nuclear Hormone Receptor Inhibitor Downregulation Estrogen receptor modulators
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / 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 / epithelial cell development / steroid hormone receptor signaling pathway / epithelial cell proliferation involved in mammary gland duct elongation ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / 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 / epithelial cell development / steroid hormone receptor signaling pathway / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / mammary gland branching involved in pregnancy / uterus development / negative regulation of smooth muscle cell apoptotic process / vagina development / TFIIB-class transcription factor binding / 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 / positive regulation of DNA-binding transcription factor activity / negative regulation of DNA-binding transcription factor activity / Nuclear signaling by ERBB4 / RNA polymerase II preinitiation complex assembly / positive regulation of nitric-oxide synthase activity / 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 / negative regulation of canonical NF-kappaB signal transduction / ESR-mediated signaling / negative regulation of miRNA transcription / TBP-class protein binding / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / transcription corepressor binding / transcription coregulator binding / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / transcription coactivator binding / male gonad development / nuclear receptor activity / positive regulation of fibroblast proliferation / 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 / positive regulation of cytosolic calcium ion concentration / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of inflammatory response / DNA-binding transcription activator activity, RNA polymerase II-specific / 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 / calmodulin binding / Extra-nuclear estrogen signaling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin remodeling / 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 / cytoplasm / cytosol
Similarity search - Function
Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / Estrogen receptor/oestrogen-related receptor / : / Retinoid X Receptor / Retinoid X Receptor / Nuclear hormone receptor ...Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / 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-H8W / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsScott, J.S. / Bailey, A. / Buttar, D. / Carbajo, R.J. / Curwen, J. / Davies, R.D.M. / Degorce, S.L. / Donald, C. / Gangl, E. / Greenwood, R. ...Scott, J.S. / Bailey, A. / Buttar, D. / Carbajo, R.J. / Curwen, J. / Davies, R.D.M. / Degorce, S.L. / Donald, C. / Gangl, E. / Greenwood, R. / Groombridge, S.D. / Johnson, T. / Lamont, S. / Lawson, M. / Lister, A. / Morrow, C. / Moss, T. / Pink, J.H. / Polanski, R.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Tricyclic Indazoles-A Novel Class of Selective Estrogen Receptor Degrader Antagonists.
Authors: Scott, J.S. / Bailey, A. / Buttar, D. / Carbajo, R.J. / Curwen, J. / Davey, P.R.J. / Davies, R.D.M. / Degorce, S.L. / Donald, C. / Gangl, E. / Greenwood, R. / Groombridge, S.D. / Johnson, T. ...Authors: Scott, J.S. / Bailey, A. / Buttar, D. / Carbajo, R.J. / Curwen, J. / Davey, P.R.J. / Davies, R.D.M. / Degorce, S.L. / Donald, C. / Gangl, E. / Greenwood, R. / Groombridge, S.D. / Johnson, T. / Lamont, S. / Lawson, M. / Lister, A. / Morrow, C.J. / Moss, T.A. / Pink, J.H. / Polanski, R.
History
DepositionNov 27, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 23, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 6, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 24, 2019Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3May 15, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.oper_expression / _pdbx_struct_assembly_prop.value
Remark 650HELIX DETERMINATION METHOD: MOE
Remark 700SHEET DETERMINATION METHOD: MOE

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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)27,4702
Polymers27,0931
Non-polymers3771
Water1,78399
1
A: Estrogen receptor
hetero molecules

A: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9414
Polymers54,1862
Non-polymers7552
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation11_555-x+y,y,-z+1/21
Buried area3010 Å2
ΔGint-15 kcal/mol
Surface area20380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.353, 58.353, 275.443
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-755-

HOH

21A-790-

HOH

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Components

#1: Protein Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 27092.807 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P03372
#2: Chemical ChemComp-H8W / 3-[4-[(6~{R})-7-(2-methylpropyl)-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]phenyl]propanoic acid


Mass: 377.479 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 2.5 Å3/Da / Density % sol: 50.77 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: #61 WELL D5: 12% PEG 3350, 0.16M MGCL2, 0.08M PCTP PH6.5, 0.2M LICL

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Data collection

DiffractionMean temperature: 110 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.84→137.72 Å / Num. obs: 25479 / % possible obs: 100 % / Redundancy: 17.5 % / Net I/σ(I): 27.6
Reflection shellResolution: 1.84→2.06 Å / Mean I/σ(I) obs: 6.4 / Num. unique obs: 1742 / % possible all: 100

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
REFMAC5.7.0032refinement
Aimlessdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.84→50.53 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.928 / SU B: 5.824 / SU ML: 0.089 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.125 / ESU R Free: 0.129 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23945 1293 5.1 %RANDOM
Rwork0.18975 ---
obs0.19223 24068 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 30.284 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20.27 Å20 Å2
2--0.27 Å20 Å2
3----0.86 Å2
Refinement stepCycle: LAST / Resolution: 1.84→50.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1865 0 28 99 1992
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0181931
X-RAY DIFFRACTIONr_bond_other_d0.0011861
X-RAY DIFFRACTIONr_angle_refined_deg1.7552617
X-RAY DIFFRACTIONr_angle_other_deg0.9424269
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.177234
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.95779
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.24345
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6039
X-RAY DIFFRACTIONr_chiral_restr0.116308
X-RAY DIFFRACTIONr_gen_planes_refined0.0092149
X-RAY DIFFRACTIONr_gen_planes_other0.001418
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_it2.174945
X-RAY DIFFRACTIONr_mcbond_other2.171944
X-RAY DIFFRACTIONr_mcangle_it3.1161176
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.241986
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.7671427
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: 1.84→1.888 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.285 89 -
Rwork0.221 1742 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 12.724 Å / Origin y: 34.06 Å / Origin z: 69.522 Å
111213212223313233
T0.008 Å2-0.013 Å2-0.001 Å2-0.04 Å2-0.001 Å2--0.036 Å2
L0.479 °2-0.456 °2-0.151 °2-0.441 °20.193 °2--0.69 °2
S-0.009 Å °-0.004 Å °0.029 Å °0.004 Å °0.013 Å °-0.017 Å °-0.017 Å °0.137 Å °-0.004 Å °

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