Molecular Dynamics shows Antagonist Destabilizes Coactivator Binding to Androgen Receptor

Click on figure to view movie of trajectory. (Requires QuickTime)

Comparison of structural and dynamic deformations of the AF2 site in DHT and Bicalutamide bound AR as well as the Apo state. Met 734 and Met 894 are colored green, while the residues comprising the "charge clamp" Glu 897, and Lys 720 are colored red and blue respectively. The formation of the well defined pocket comprising the AF2 site on binding of DHT can be seen by comparing the sites in the figures and especially in the movies. Inspection of the MD trajectory reveals that the AF2 site is significantly more stable in the hormone bound structure. In both the apo and antagonist bound structures it is severely distorted, and labile, thus diminishing its ability to bind coactivator. (These movies require QuickTime to view)