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- PDB-2yhd: Human androgen receptor in complex with AF2 small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 2yhd
TitleHuman androgen receptor in complex with AF2 small molecule inhibitor
ComponentsANDROGEN RECEPTOR
KeywordsTRANSCRIPTION / ACTIVATION FUNCTION 2 SITE (AF2) / SMALL MOLECULE INHIBITOR
Function / homology
Function and homology information


male somatic sex determination / prostate induction / lateral sprouting involved in mammary gland duct morphogenesis / male genitalia morphogenesis / regulation of developmental growth / POU domain binding / positive regulation of integrin biosynthetic process / tertiary branching involved in mammary gland duct morphogenesis / animal organ formation / androgen binding ...male somatic sex determination / prostate induction / lateral sprouting involved in mammary gland duct morphogenesis / male genitalia morphogenesis / regulation of developmental growth / POU domain binding / positive regulation of integrin biosynthetic process / tertiary branching involved in mammary gland duct morphogenesis / animal organ formation / androgen binding / cellular response to testosterone stimulus / regulation of systemic arterial blood pressure / Leydig cell differentiation / epithelial cell differentiation involved in prostate gland development / positive regulation of epithelial cell proliferation involved in prostate gland development / prostate gland epithelium morphogenesis / prostate gland growth / epithelial cell morphogenesis / 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 / cellular response to steroid hormone stimulus / morphogenesis of an epithelial fold / positive regulation of intracellular estrogen receptor signaling pathway / androgen receptor signaling pathway / seminiferous tubule development / RUNX2 regulates osteoblast differentiation / nuclear steroid receptor activity / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / nuclear receptor-mediated steroid hormone signaling pathway / single fertilization / RNA polymerase II core promoter sequence-specific DNA binding / regulation of protein localization to plasma membrane / 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 / RNA polymerase II transcription regulatory region sequence-specific DNA binding / 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 / beta-catenin binding / Nuclear Receptor transcription pathway / positive regulation of miRNA transcription / transcription coactivator binding / multicellular organism growth / male gonad development / nuclear receptor activity / negative regulation of epithelial cell proliferation / cell-cell signaling / MAPK cascade / ATPase binding / DNA-binding transcription activator activity, RNA polymerase II-specific / spermatogenesis / molecular adaptor activity / in utero embryonic development / RNA polymerase II-specific DNA-binding transcription factor binding / 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 / cytoplasm / cytosol
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
4-(2,3-dihydro-1H-perimidin-2-yl)benzene-1,2-diol / TESTOSTERONE / Androgen receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsAxerioCilies, P. / Lack, N.A. / ShashiNayana, M.R. / Chan, K.H. / Yeung, A. / LeBlanc, E. / Guns, E. / Rennie, P. / Cherkasov, A.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Inhibitors of Androgen Receptor Activation Function-2 (Af2) Site Identified Through Virtual Screening.
Authors: Axerio-Cilies, P. / Lack, N.A. / Nayana, M.R. / Chan, K.H. / Yeung, A. / Leblanc, E. / Guns, E.S. / Rennie, P.S. / Cherkasov, A.
History
DepositionApr 28, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 21, 2011Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2011Group: Database references
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._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: ANDROGEN RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,7094
Polymers29,0461
Non-polymers6633
Water43224
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.530, 66.750, 73.680
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: 29046.074 Da / Num. of mol.: 1 / Fragment: LIGAND BINDING DOMAIN, RESIDUES 671-919
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PGEX / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P10275
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-TES / TESTOSTERONE


Mass: 288.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H28O2
#4: Chemical ChemComp-AV6 / 4-(2,3-dihydro-1H-perimidin-2-yl)benzene-1,2-diol / 4-{2,4-DIAZATRICYCLO[7.3.1.0]TRIDECA- 1(12),5,7,9(13),10-PENTAEN-3-YL}BENZENE-1,2-DIOL


Mass: 278.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14N2O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / 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: 2.4 Å3/Da / Density % sol: 47.4 % / Description: NONE
Crystal growpH: 7.5
Details: 0.35 M NA2HPO4/K2HPO4, 0.1 M (NH4)2HPO4, 7.0% PEG 400, 50 MM TRIS-HCL, PH 7.5.

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Data collection

DiffractionMean temperature: 294 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.98
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationMonochromator: ASYMMETRIC CUT SINGLE CRYSTAL SI(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.2→49.5 Å / Num. obs: 14010 / % possible obs: 98.8 % / Observed criterion σ(I): 2 / Redundancy: 5.2 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 11.1
Reflection shellResolution: 2.2→2.26 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 2.5 / % possible all: 90.5

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
MOSFLMdata reduction
MOSFLMdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2AM9

2am9


Resolution: 2.2→49.47 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.915 / SU B: 6.45 / SU ML: 0.163 / Cross valid method: THROUGHOUT / ESU R: 0.283 / ESU R Free: 0.224 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.25912 746 5.1 %RANDOM
Rwork0.20898 ---
obs0.21144 14010 98.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.076 Å2
Baniso -1Baniso -2Baniso -3
1-1.26 Å20 Å20 Å2
2---0.14 Å20 Å2
3----1.12 Å2
Refinement stepCycle: LAST / Resolution: 2.2→49.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2003 0 47 24 2074
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0222106
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9071.982861
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5755248
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.16923.54893
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.58415357
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5981512
X-RAY DIFFRACTIONr_chiral_restr0.1440.2315
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211573
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.0281.51248
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.93322018
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.1363858
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.774.5843
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: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.293 56 -
Rwork0.228 912 -
obs--90.47 %

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