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PDBsum entry 2q7l
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References listed in PDB file
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Key reference
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Title
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Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone.
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Authors
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E.B.Askew,
R.T.Gampe,
T.B.Stanley,
J.L.Faggart,
E.M.Wilson.
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Ref.
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J Biol Chem, 2007,
282,
25801-25816.
[DOI no: ]
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PubMed id
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Abstract
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The androgen receptor (AR) is transcriptionally activated by high affinity
binding of testosterone (T) or its 5alpha-reduced metabolite,
dihydrotestosterone (DHT), a more potent androgen required for male reproductive
tract development. The molecular basis for the weaker activity of T was
investigated by determining T-bound ligand binding domain crystal structures of
wild-type AR and a prostate cancer somatic mutant complexed with the AR FXXLF or
coactivator LXXLL peptide. Nearly identical interactions of T and DHT in the AR
ligand binding pocket correlate with similar rates of dissociation from an AR
fragment containing the ligand binding domain. However, T induces weaker AR
FXXLF and coactivator LXXLL motif interactions at activation function 2 (AF2).
Less effective FXXLF motif binding to AF2 accounts for faster T dissociation
from full-length AR. T can nevertheless acquire DHT-like activity through an AR
helix-10 H874Y prostate cancer mutation. The Tyr-874 mutant side chain mediates
a new hydrogen bonding scheme from exterior helix-10 to backbone protein core
helix-4 residue Tyr-739 to rescue T-induced AR activity by improving AF2 binding
of FXXLF and LXXLL motifs. Greater AR AF2 activity by improved core helix
interactions is supported by the effects of melanoma antigen gene protein-11, an
AR coregulator that binds the AR FXXLF motif and targets AF2 for activation. We
conclude that T is a weaker androgen than DHT because of less favorable
T-dependent AR FXXLF and coactivator LXXLL motif interactions at AF2.
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Figure 8.
FIGURE 8. Potential A-ring and water mediated H-bonding
schemes for T and DHT. Predicted A-ring H-bond distances and
angles are shown based on the tetrahedral geometry of conserved
structural water HOH1 (see Footnote 3 and see Table 4).
Arrowhead with black dashed lines indicate the direction of
donated H-bonds and orange dashed lines designate potential
interactions with neighboring polar atoms of WT AR LBD bound to
T and AR-(20-30) FXXLF peptide (tan) (A); WT AR LBD bound to DHT
and GRIP-1-(740-752) LXXLL peptide (green) (42) (B); and the
superimposition of A and B (C). Superior hydrophilic properties
and a shorter distance are thought to enhance the HOH1 to T
3-keto O H-bond over that in DHT.
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Figure 11.
FIGURE 11. Structural differences between the steroid and
nonsteroidal ligand binding pockets. Superimposition of WT AR
LBD crystal structures bound with an FXXLF peptide and T
(brown), DHT (green) (18), R1881 (magenta) (4), and S-1
bicalutamide agonist analog (cyan) (43) and AR-H874Y LBD bound
to the AR FXXLF peptide and T (yellow). The C-19 bridgehead
methyl group on T and DHT forces the Met-745 and Trp-741 side
chains away from the steroid A-ring. For R1881 and S-1, the
absence of an equivalent methyl group allows these side chains
to adopt different rotamers that fill the vacated space above
ring A^4. The para-fluoro phenyl group on S1 extends into the
space between helix-12 Met-895 and helix-5 Met-742 and directs
Trp-741 to a third unique conformation. Appropriate para-phenyl
substituents are thought to stabilize the AR LBD core by
interacting with HOH3 (43).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
25801-25816)
copyright 2007.
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