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PDBsum entry 2ax6
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Transcription
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PDB id
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2ax6
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References listed in PDB file
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Key reference
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Title
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Structural basis for accommodation of nonsteroidal ligands in the androgen receptor.
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Authors
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C.E.Bohl,
D.D.Miller,
J.Chen,
C.E.Bell,
J.T.Dalton.
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Ref.
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J Biol Chem, 2005,
280,
37747-37754.
[DOI no: ]
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PubMed id
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Abstract
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The mechanism by which the androgen receptor (AR) distinguishes between agonist
and antagonist ligands is poorly understood. AR antagonists are currently used
to treat prostate cancer. However, mutations commonly develop in patients that
convert these compounds to agonists. Recently, our laboratory discovered
selective androgen receptor modulators, which structurally resemble the
nonsteroidal AR antagonists bicalutamide and hydroxyflutamide but act as
agonists for the androgen receptor in a tissue-selective manner. To investigate
why subtle structural changes to both the ligand and the receptor (i.e.
mutations) result in drastic changes in activity, we studied structure-activity
relationships for nonsteroidal AR ligands through crystallography and
site-directed mutagenesis, comparing bound conformations of R-bicalutamide,
hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1 and
R-3. These studies provide the first crystallographic evidence of the mechanism
by which nonsteroidal ligands interact with the wild type AR. We have shown that
changes induced to the positions of Trp-741, Thr-877, and Met-895 allow for
ligand accommodation within the AR binding pocket and that a water-mediated
hydrogen bond to the backbone oxygen of Leu-873 and the ketone of
hydroxyflutamide is present when bound to the T877A AR variant. Additionally, we
demonstrated that R-bicalutamide stimulates transcriptional activation in AR
harboring the M895T point mutation. As a whole, these studies provide critical
new insight for receptor-based drug design of nonsteroidal AR agonists and
antagonists.
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Figure 5.
FIGURE 5. Ligand-induced changes to Trp-741 and Met-895 in
stereo overlay and individually as space-fill representations.
a, comparison of the changes induced by DHT (slate) (Protein
Data Bank code 1I37 [PDB]
), R1881 (ruby) (Protein Data Bank code 1XQ2), R-3 (gold), and
S-1 (green) to the Trp-741, Met-745, Met-895 side chains. Notice
the different location of Met-745 in the DHT-bound structure
from displacement by the 19-methyl group, which causes the
Trp-741 side chain to also move relative to its position in
R1881. The Trp-741 indole ring is positioned similarly in R1881-
and R-3-complexed structures; however, the bromine atom on R-3
displaces the Met-895 side chain. Also notice the change in
position of the Trp-741 indole ring to allow accommodation of
the S-1 B-ring. b, changes in the position of Met-895 in the
W741L AR bound to S-1 (black) and R-bicalutamide (yellow).
Compared with the WT-S-1 complex, Met-895 moves toward the
Leu-741 side chain in the W741L-S-1 complex, compensating for
the loss of bulk in this mutant. In the W741L-R-bicalutamide
complex, the Met-895 side chain is wedged between the Leu-741
and the sulfonyl group of R-bicalutamide. Notice that the
position of the Met-895 side chain in the WT-S-1 complex would
be sterically precluded by the sulfonyl group of R-bicalutamide
in the presence of Trp-741.
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Figure 6.
FIGURE 6. Ligand interactions with helices 3, 5, 11, and
12. a, WT AR LBD complexed to S-1 (green) rotated 180° about
the y-axis relative to Fig. 3, c and d. Helix 3, blue; helices
4/5, Trp741, purple; helix 11, Thr-877, red; helix 12, Met-895,
gold. b, surface contacts of the secondary structural elements
of the WT AR LBD with S-1. Notice the contacts from Trp-741,
Thr-877, and Met-895 on helices 5, 11, and 12, respectively. c,
surface contacts of the secondary structural elements of the
W741L AR LBD with R-bicalutamide. Notice the loss of contacts of
helix 5 from the loss of bulk in the W741L mutant and that helix
12 increases contacts to the ligand as a result of Met-895
repositioning. Also notice the location of the sulfonyl group of
R-bicalutamide, which increases the binding pocket size relative
to S-1.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
37747-37754)
copyright 2005.
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