Alternatives to Antiandrogens

Principal Investigators - Robert Fletterick, PhD | Marc Shuman, MD

Our goal is to use X-ray crystallography to uncover the structural principles underlying androgen action, so that we may ultimately use those principles to design new and more effective antiandrogens for use against prostate cancer.

In both health and disease, gene activation by androgen receptor (AR) requires coactivator proteins that interact with AR at the ligand binding domain (LBD) via short peptide sequences, or at the AR N-terminal domain (NTD). Once bound to AR, these coactivators mediate the formation of a large multiprotein complex that unpackages AR-responsive genes from chromatin and activates the basal transcription machinery. The interactions between AR and coactivators are unknown, and we intend to elucidate them by determining structures of AR NTD bound to NTD-interacting coregulators of the p160 family and of AR LBD bound to two classes of peptides: actual interaction domains from coactivators known to bind AR LBD, and artificial, tight-binding peptides discovered by library screening. Visualizing two of the former class of LDB-binding peptides will enable us to describe the precise interactions which take place in vivo, whereas the latter class will enable us to better determine which features of those binding surfaces are most important in producing both specificity and plasticity in binding.