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- EMDB-25133: Androgen receptor bound to DNA - Splayed state -

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Basic information

Entry
Database: EMDB / ID: EMD-25133
TitleAndrogen receptor bound to DNA - Splayed state
Map data
Sample
  • Complex: Androgen receptor bound to DNA - Splayed state
    • DNA: ARE DNA
    • Protein or peptide: Androgen receptor
Biological speciesMus musculus (house mouse) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 9.1 Å
AuthorsWasmuth EV / Vanden Broeck A / Klinge S / Sawyers CL
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM140264 United States
Department of Defense (DOD, United States)W81XWH-18-1-0182 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Mol Cell / Year: 2022
Title: Allosteric interactions prime androgen receptor dimerization and activation.
Authors: Elizabeth V Wasmuth / Arnaud Vanden Broeck / Justin R LaClair / Elizabeth A Hoover / Kayla E Lawrence / Navid Paknejad / Kyrie Pappas / Doreen Matthies / Biran Wang / Weiran Feng / Philip A ...Authors: Elizabeth V Wasmuth / Arnaud Vanden Broeck / Justin R LaClair / Elizabeth A Hoover / Kayla E Lawrence / Navid Paknejad / Kyrie Pappas / Doreen Matthies / Biran Wang / Weiran Feng / Philip A Watson / John C Zinder / Wouter R Karthaus / M Jason de la Cruz / Richard K Hite / Katia Manova-Todorova / Zhiheng Yu / Susan T Weintraub / Sebastian Klinge / Charles L Sawyers /
Abstract: The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers display AR ...The androgen receptor (AR) is a nuclear receptor that governs gene expression programs required for prostate development and male phenotype maintenance. Advanced prostate cancers display AR hyperactivation and transcriptome expansion, in part, through AR amplification and interaction with oncoprotein cofactors. Despite its biological importance, how AR domains and cofactors cooperate to bind DNA has remained elusive. Using single-particle cryo-electron microscopy, we isolated three conformations of AR bound to DNA, showing that AR forms a non-obligate dimer, with the buried dimer interface utilized by ancestral steroid receptors repurposed to facilitate cooperative DNA binding. We identify novel allosteric surfaces which are compromised in androgen insensitivity syndrome and reinforced by AR's oncoprotein cofactor, ERG, and by DNA-binding motifs. Finally, we present evidence that this plastic dimer interface may have been adopted for transactivation at the expense of DNA binding. Our work highlights how fine-tuning AR's cooperative interactions translate to consequences in development and disease.
History
DepositionOct 11, 2021-
Header (metadata) releaseMay 4, 2022-
Map releaseMay 4, 2022-
UpdateJun 22, 2022-
Current statusJun 22, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25133.png

Downloads & links

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Map

FileDownload / File: emd_25133.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
2.14 Å/pix.
x 128 pix.
= 273.664 Å		2.14 Å/pix.
x 128 pix.
= 273.664 Å		2.14 Å/pix.
x 128 pix.
= 273.664 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 2.138 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.037
Minimum - Maximum-0.031414554 - 0.21738802
Average (Standard dev.)0.0010353605 (±0.007160771)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 273.664 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_25133_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_25133_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Androgen receptor bound to DNA - Splayed state

EntireName: Androgen receptor bound to DNA - Splayed state
Components
  • Complex: Androgen receptor bound to DNA - Splayed state
    • DNA: ARE DNA
    • Protein or peptide: Androgen receptor

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Supramolecule #1: Androgen receptor bound to DNA - Splayed state

SupramoleculeName: Androgen receptor bound to DNA - Splayed state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: ARE DNA

MacromoleculeName: ARE DNA / type: dna / ID: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
SequenceString:
TAGCGTGGCC AGAACATCAT GTTCTCCGGT GCGAT

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Macromolecule #2: Androgen receptor

MacromoleculeName: Androgen receptor / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GSDYYFPPQK TCLICGDEAS GCHYGALTCG SCKVFFKRAA EGKQKYL CA SRNDCTIDKF RRKNCPSCRL RKCYEAGMTL GARKLKKLGN LKLQEEGENS NAGSPTEDPS QKMTVSHI E GYECQPIFLN VLEAIEPGVV CAGHDNNQPD SFAALLSSLN ELGERQLVHV ...String:
GSDYYFPPQK TCLICGDEAS GCHYGALTCG SCKVFFKRAA EGKQKYL CA SRNDCTIDKF RRKNCPSCRL RKCYEAGMTL GARKLKKLGN LKLQEEGENS NAGSPTEDPS QKMTVSHI E GYECQPIFLN VLEAIEPGVV CAGHDNNQPD SFAALLSSLN ELGERQLVHV VKWAKALPGF RNLHVDDQM AVIQYSWMGL MVFAMGWRSF TNVNSRMLYF APDLVFNEYR MHKSRMYSQC VRMRHLSQEF GWLQITPQEF LCMKALLLF SIIPVDGLKN QKFFDELRMN YIKELDRIIA CKRKNPTSCS RRFYQLTKLL DSVQPIAREL H QFTFDLLI KSHMVSVDFP EMMAEIISVQ VPKILSGKVK PIYFHTQ

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 61.27 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 17798
Final reconstructionResolution.type: BY AUTHOR / Resolution: 9.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 53169
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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