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Structural Characterization and Ligand Specific Protein Interactions of Androgen Receptor

Please use this identifier to cite or link to this item: http://hdl.handle.net/1811/31785

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Title: Structural Characterization and Ligand Specific Protein Interactions of Androgen Receptor
Creators: Baker, Stacy
Advisor: Dalton, James
Issue Date: 2008-03
Abstract: Background: Androgen receptor (AR) is a protein in the human body that binds various steroidal androgens such as testosterone and causes specific anabolic and androgenic activities. Current methods of androgen therapy are limited in use because of their inability to target anabolic versus androgenic activities. Selective androgen receptor modulators (SARMs) are nonsteroidal AR ligands that hold clinical promise in that they have the ability to selectively target anabolic versus androgenic activities, because they have the ability to act as agonists and antagonists in various tissues. Despite all that is known about SARM pharmacology, there is limited information about their structure, stability, and protein-protein interactions. Study Design and Methods: The question arises of whether or not two known SARMs (007 and 014) differ in their biochemical properties when bound to AR. To explore the question of which complex is the most stable, AR-ligand complexes (i.e., AR-007 and AR-014) were formed with the SARMs and they were exposed to heat to determine if the two had different degradation rates. To determine differences in three-dimensional conformation, the complexes were degraded by typsin to explore if they yielded different patterns of degradation. Finally, to determine whether or not the two complexes have different protein-protein interactions, heat shock protein 70 (hsp70) was measured via a Western blot technique to determine if the two complexes have different levels of association with hsp70. Results: AR-007 degraded more quickly than AR-014 when exposed to heat. AR-007 and AR-014 were broken down by trypsin in a similar fashion. AR-007 and AR-014 seem to have a tighter and more coiled conformation than AR-DHT (dihydrotestosterone), which was used as a positive control, because AR-DHT was broken down more readily by trypsin than the AR-SARM complexes. The AR-007 complex also had a stronger association with hsp70 than the AR-014 complex. Conclusion: The faster degradation of AR-007 when exposed to heat and its stronger association with hsp70 indicates that it is the least stable out of the two SARM complexes with AR. We conclude that SARM-induced conformational changes in the AR contribute to their differing pharmacology from steroidal androgens. These conformational changes are ligand-specific and affect the stability of the AR and its interactions with other intracellular proteins.
Embargo: No embargo
Series/Report no.: The Ohio State University. School of Allied Medical Professions Honors Theses; 2008
Keywords: androgen receptor
selective androgen receptor modulators
Sponsors: Dr. James Dalton's laboratory
School of Allied Medical Professions
URI: http://hdl.handle.net/1811/31785
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