Targeting alpha-helix based protein interactions : nuclear receptors as a case study

This book chapter highlights the important role played by a-helical structures in controlling protein-protein interactions (PPIs). First a brief discussion of the fundamental aspects of the a-helix structure is provided, including a word on nomenclature. Then some examples of different proteins involved in a-helical PPIs – for example Bcl-2, p53 and HIF-1a– are introduced alongside current methods for inhibiting these interactions, which typically rely on small lipophilic drug molecules, oligomeric structures or modified peptides. Next, nuclear hormone receptors will be discussed as quintessential a-helix mediated PPIs. By covering two of the most widely studied members of this intriguing protein class – the estrogen receptor (ER) and the androgen receptor (AR)– the important structural features of nuclear receptors will be discussed, and the significance of PPIs in terms of the binding of a-helical coregulator proteins highlighted. Finally, the chapter will round off with a discussion on how the principles of a-helicity have helped in the design of peptide-based and non-peptidic inhibitors of PPIs for drug discovery. In this case, the reader's attention will be mainly drawn to recent advances in the field.