PERSPECTIVES interact with and regulate an array of downstream signaling proteins such as phospholipase C–β, G protein–coupled receptor kinase 2 (GRK2), and phosphatidylinositol 3-kinase. These structurally diverse proteins bind (or are expected to bind) to a surface of Gβγ that overlaps the binding site of Gα (10–14), accounting for the ability of Gα to keep Gβγ from signaling in the absence of extracellular signals (by forming the inactive Gαβγ heterotrimer).

Despite the large surface area of Gβγ that is buried within the Gαβγ complex, it was previously shown that small peptides derived from a phage display library could differentially inhibit the binding of Gβγ to Gα and to its various downstream targets. The peptides bind to a site in Gβγ1 that lies near the center of the surface known to interact with Gα and the effector protein GRK2 (15, 16). Although peptides are not usually good drug candidates, they can still be very useful in defining the functional sites on protein surfaces that can then be targeted by small-molecule drugs (17). Accordingly, Bonacci et al. used the structure of Gβγ bound to one of the phage display peptides to define the hot spot of Gβγ (see the fig-