2axa: Difference between revisions
New page: left|200px<br /> <applet load="2axa" size="450" color="white" frame="true" align="right" spinBox="true" caption="2axa, resolution 1.80Å" /> '''Crystal Structure O... |
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[[Image:2axa.gif|left|200px]]<br /> | [[Image:2axa.gif|left|200px]]<br /><applet load="2axa" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2axa, resolution 1.80Å" /> | caption="2axa, resolution 1.80Å" /> | ||
'''Crystal Structure Of The Androgen Receptor Ligand Binding Domain In Complex With S-1'''<br /> | '''Crystal Structure Of The Androgen Receptor Ligand Binding Domain In Complex With S-1'''<br /> | ||
==Overview== | ==Overview== | ||
The mechanism by which the androgen receptor (AR) distinguishes between | 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. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2AXA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FHM as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 2AXA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FHM:'>FHM</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AXA OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bell, C | [[Category: Bell, C E.]] | ||
[[Category: Bohl, C | [[Category: Bohl, C E.]] | ||
[[Category: Chen, J.]] | [[Category: Chen, J.]] | ||
[[Category: Dalton, J | [[Category: Dalton, J T.]] | ||
[[Category: Miller, D | [[Category: Miller, D D.]] | ||
[[Category: FHM]] | [[Category: FHM]] | ||
[[Category: transcription]] | [[Category: transcription]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:31:56 2008'' | ||
Revision as of 17:31, 21 February 2008
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Crystal Structure Of The Androgen Receptor Ligand Binding Domain In Complex With S-1
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Androgen insensitivity OMIM:[313700], Breast cancer, male, with Reifenstein syndrome OMIM:[313700], Hypospadias, perineal OMIM:[313700], Prostate cancer OMIM:[313700], Prostate cancer, susceptibility to OMIM:[313700], Spinal and bulbar muscular atrophy of Kennedy OMIM:[313700]
About this StructureAbout this Structure
2AXA is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for accommodation of nonsteroidal ligands in the androgen receptor., Bohl CE, Miller DD, Chen J, Bell CE, Dalton JT, J Biol Chem. 2005 Nov 11;280(45):37747-54. Epub 2005 Aug 29. PMID:16129672
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