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- PDB-8e1a: Structure-based study to overcome cross-reactivity of novel andro... -

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Basic information

Entry
Database: PDB / ID: 8e1a
TitleStructure-based study to overcome cross-reactivity of novel androgen receptor inhibitors
ComponentsAndrogen receptor
KeywordsTRANSCRIPTION / androgen receptor / agonist / antagonist / HORMONE RECEPTOR
Function / homology
Function and homology information


male somatic sex determination / prostate induction / lateral sprouting involved in mammary gland duct morphogenesis / male genitalia morphogenesis / POU domain binding / negative regulation of integrin biosynthetic process / regulation of developmental growth / positive regulation of integrin biosynthetic process / tertiary branching involved in mammary gland duct morphogenesis / animal organ formation ...male somatic sex determination / prostate induction / lateral sprouting involved in mammary gland duct morphogenesis / male genitalia morphogenesis / POU domain binding / negative regulation of integrin biosynthetic process / regulation of developmental growth / positive regulation of integrin biosynthetic process / tertiary branching involved in mammary gland duct morphogenesis / animal organ formation / androgen binding / Leydig cell differentiation / regulation of systemic arterial blood pressure / epithelial cell morphogenesis / prostate gland growth / epithelial cell differentiation involved in prostate gland development / positive regulation of epithelial cell proliferation involved in prostate gland development / prostate gland epithelium morphogenesis / cellular response to testosterone stimulus / membraneless organelle assembly / RNA polymerase II general transcription initiation factor binding / positive regulation of insulin-like growth factor receptor signaling pathway / positive regulation of transcription by RNA polymerase III / morphogenesis of an epithelial fold / cellular response to steroid hormone stimulus / positive regulation of intracellular estrogen receptor signaling pathway / seminiferous tubule development / RUNX2 regulates osteoblast differentiation / androgen receptor signaling pathway / cellular response to estrogen stimulus / mammary gland alveolus development / single fertilization / estrogen response element binding / nuclear receptor-mediated steroid hormone signaling pathway / positive regulation of phosphorylation / regulation of protein localization to plasma membrane / RNA polymerase II core promoter sequence-specific DNA binding / intracellular receptor signaling pathway / estrogen receptor signaling pathway / steroid binding / insulin-like growth factor receptor signaling pathway / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / epithelial cell proliferation / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of cell differentiation / SUMOylation of intracellular receptors / molecular condensate scaffold activity / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / transcription coactivator binding / G protein-coupled receptor activity / beta-catenin binding / multicellular organism growth / Nuclear Receptor transcription pathway / positive regulation of miRNA transcription / nuclear receptor activity / male gonad development / negative regulation of epithelial cell proliferation / positive regulation of NF-kappaB transcription factor activity / MAPK cascade / cell-cell signaling / ATPase binding / DNA-binding transcription activator activity, RNA polymerase II-specific / spermatogenesis / molecular adaptor activity / RNA polymerase II-specific DNA-binding transcription factor binding / in utero embryonic development / transcription by RNA polymerase II / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription cis-regulatory region binding / positive regulation of MAPK cascade / Ub-specific processing proteases / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / signaling receptor binding / negative regulation of cell population proliferation / positive regulation of cell population proliferation / chromatin binding / positive regulation of gene expression / chromatin / positive regulation of DNA-templated transcription / 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 / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Androgen receptor / Androgen receptor / : / Retinoid X Receptor / Retinoid X 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 ...Androgen receptor / Androgen receptor / : / Retinoid X Receptor / Retinoid X 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-3E0 / Androgen receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsLallous, N. / Li, H. / Radaeva, M. / Dalal, K. / Leblanc, E. / Ban, F. / Ciesielski, F. / Chow, B. / Morin, M. / Singh, K. ...Lallous, N. / Li, H. / Radaeva, M. / Dalal, K. / Leblanc, E. / Ban, F. / Ciesielski, F. / Chow, B. / Morin, M. / Singh, K. / Rennie, P.S. / Cherkasov, A.
Funding support Canada, 1items
OrganizationGrant numberCountry
Other private272111 Canada
CitationJournal: Cells / Year: 2022
Title: Structure-Based Study to Overcome Cross-Reactivity of Novel Androgen Receptor Inhibitors.
Authors: Radaeva, M. / Li, H. / LeBlanc, E. / Dalal, K. / Ban, F. / Ciesielski, F. / Chow, B. / Morin, H. / Awrey, S. / Singh, K. / Rennie, P.S. / Lallous, N. / Cherkasov, A.
History
DepositionAug 10, 2022Deposition site: RCSB / Processing site: RCSB
SupersessionSep 14, 2022ID: 4U4K
Revision 1.0Sep 14, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 16, 2022Group: Advisory / Category: pdbx_database_PDB_obs_spr
Revision 1.3Nov 30, 2022Group: Advisory / Category: pdbx_database_PDB_obs_spr
Revision 1.4Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Androgen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6846
Polymers32,1411
Non-polymers5435
Water4,630257
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.953, 65.762, 69.128
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Androgen receptor / Dihydrotestosterone receptor / Nuclear receptor subfamily 3 group C member 4


Mass: 32141.469 Da / Num. of mol.: 1 / Fragment: Ligand-binding domain residues 664-919
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AR, DHTR, NR3C4 / Production host: Escherichia coli (E. coli) / References: UniProt: P10275
#2: Chemical ChemComp-3E0 / 4-[4-(3-fluoro-2-methoxyphenyl)-1,3-thiazol-2-yl]morpholine


Mass: 294.345 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15FN2O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 257 / 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: 1.94 Å3/Da / Density % sol: 36.7 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1M Hepes, 0.4-1M Sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9725 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 2, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9725 Å / Relative weight: 1
ReflectionResolution: 1.2→40 Å / Num. obs: 87299 / % possible obs: 97 % / Redundancy: 6.2 % / Rsym value: 0.04 / Net I/σ(I): 22.84
Reflection shellResolution: 1.2→1.27 Å / Mean I/σ(I) obs: 3.83 / Num. unique obs: 72860 / Rsym value: 0.397

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in house structure

Resolution: 1.2→40 Å / Cor.coef. Fo:Fc: 0.982 / Cor.coef. Fo:Fc free: 0.976 / SU B: 1.179 / SU ML: 0.024 / Cross valid method: THROUGHOUT / ESU R: 0.034 / ESU R Free: 0.034 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.15146 3835 5 %RANDOM
Rwork0.12417 ---
obs0.12555 72860 97.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 15.982 Å2
Baniso -1Baniso -2Baniso -3
1-2.02 Å20 Å2-0 Å2
2---0.82 Å20 Å2
3----1.19 Å2
Refinement stepCycle: 1 / Resolution: 1.2→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2032 0 36 257 2325
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0192255
X-RAY DIFFRACTIONr_bond_other_d0.0020.022191
X-RAY DIFFRACTIONr_angle_refined_deg2.1471.9653067
X-RAY DIFFRACTIONr_angle_other_deg1.31235041
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2825286
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.59623.524105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.49615406
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5171516
X-RAY DIFFRACTIONr_chiral_restr0.1390.2331
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212575
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02558
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
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_restr9.04434446
X-RAY DIFFRACTIONr_sphericity_free52.476555
X-RAY DIFFRACTIONr_sphericity_bonded13.48954581
LS refinement shellResolution: 1.2→1.231 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.228 219 -
Rwork0.2 4379 -
obs--80.09 %
Refinement TLS params.Method: refined / Origin x: 20.8599 Å / Origin y: 5.7224 Å / Origin z: 10.7082 Å
111213212223313233
T0.0001 Å20.0002 Å2-0.0002 Å2-0.0084 Å20.0005 Å2--0.0125 Å2
L0.0152 °2-0.0016 °2-0.0029 °2-0.0134 °20.0063 °2--0.0374 °2
S0.0008 Å °-0.0007 Å °-0.0013 Å °0 Å °-0.0006 Å °0.0001 Å °0.0004 Å °-0.0007 Å °-0.0001 Å °

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