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- PDB-6suo: ERa_L536S (L536S/C381S/C471S,C530S) in complex with a tricyclic i... -

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Basic information

Entry
Database: PDB / ID: 6suo
TitleERa_L536S (L536S/C381S/C471S,C530S) in complex with a tricyclic indole (compound 6)
ComponentsEstrogen receptor
KeywordsGENE REGULATION / oestrogen receptor / oestrogen binding domain
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-LVH / Estrogen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.74 Å
AuthorsBreed, J.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Building Bridges in a Series of Estrogen Receptor Degraders: An Application of Metathesis in Medicinal Chemistry.
Authors: Scott, J.S. / Breed, J. / Carbajo, R.J. / Davey, P.R. / Greenwood, R. / Huynh, H.K. / Klinowska, T. / Morrow, C.J. / Moss, T.A. / Polanski, R. / Nissink, J.W.M. / Varnes, J. / Yang, B.
History
DepositionSep 16, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 11, 2020Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Revision 1.2May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)58,2244
Polymers57,3112
Non-polymers9132
Water1,54986
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2490 Å2
ΔGint-9 kcal/mol
Surface area18700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.180, 51.360, 82.780
Angle α, β, γ (deg.)90.000, 91.530, 90.000
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


Mass: 28655.521 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli (E. coli) / References: UniProt: P03372
#2: Chemical ChemComp-LVH / (~{E})-3-[3,5-bis(fluoranyl)-4-[(1~{R},3~{R})-2-(2-fluoranyl-2-methyl-propyl)-1,3-dimethyl-4,9-dihydro-3~{H}-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid


Mass: 456.500 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H27F3N2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.93 Å3/Da / Density % sol: 36.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 3350, magnesium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.74→53.07 Å / Num. obs: 42899 / % possible obs: 93.4 % / Redundancy: 3.1 % / Biso Wilson estimate: 36.24 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.033 / Rpim(I) all: 0.021 / Rrim(I) all: 0.04 / Net I/σ(I): 15.6 / Num. measured all: 133682
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.74-1.791.90.649410021040.5710.5650.8651.162.8
7.78-53.073.30.016179455010.010.01949.397.8

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
Aimlessdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.74→53.07 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.931 / SU R Cruickshank DPI: 0.131 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.128 / SU Rfree Blow DPI: 0.118 / SU Rfree Cruickshank DPI: 0.12
RfactorNum. reflection% reflectionSelection details
Rfree0.244 2120 4.94 %RANDOM
Rwork0.221 ---
obs0.223 42899 93.3 %-
Displacement parametersBiso max: 123.93 Å2 / Biso mean: 41.99 Å2 / Biso min: 20.59 Å2
Baniso -1Baniso -2Baniso -3
1-1.5613 Å20 Å21.1148 Å2
2--1.9315 Å20 Å2
3----3.4928 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 1.74→53.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3154 0 66 86 3306
Biso mean--45.27 38.48 -
Num. residues----430
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1092SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes543HARMONIC5
X-RAY DIFFRACTIONt_it3288HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion447SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3906SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3288HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4478HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion2.6
X-RAY DIFFRACTIONt_other_torsion16.27
LS refinement shellResolution: 1.74→1.76 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2146 38 4.43 %
Rwork0.2296 820 -
all0.229 858 -
obs--59.75 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.0527-0.56810.37241.7721-0.30791.31170.09480.03930.0116-0.1152-0.01130.10240.0886-0.067-0.0835-0.22120.0201-0.0037-0.2273-0.0044-0.17429.24355.651522.067
22.6985-0.0219-0.69490.9540.16151.73060.0456-0.00610.1381-0.04190.109-0.08060.38880.4371-0.1546-0.19950.1532-0.0583-0.149-0.0751-0.208652.9357-5.73320.7718
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A303 - 552
2X-RAY DIFFRACTION2{ B|* }B310 - 544

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