Autoinhibition of Rho GTPase Effectors as a Target for Small Molecule Inhibitors

The regulation of N-WASP activity involves the binding of an activator (Cdc42) to the autoinhibitory element (GBD), which displaces this element from the functional domain (VCA). Strikingly, a similar paradigm can be found in the regulation of many other proteins including other Rho family GTPase effectors, such as members of the group I p21-activated kinases (Paks) and the diaphanous-related formins (DRF). The shared regulatory strategy of autoinhibition observed in each of these proteins along with our understanding of N-WASP inhibition by wiskostatin suggests that the conformational changes of group I Paks and DRFs could be targets for small-molecule inhibition. Indeed, we have proposed that, in general, proteins that adopt autoinhibited conformations could be susceptible to small molecules that stabilize the inhibited conformation (Peterson and Golemis 2004). Importantly, as illustrated by N-WASP, proteins targeted by this strategy need not be enzymes or possess already known small-molecule binding sites.

Small-molecule inhibitors that target Paks and DRFs could be used to dissect the specific role of these effectors downstream of Rho GTPases. In addition, chemical inhibition of Pak1 may serve as the basis for the development of novel therapeutics, as there is increasing evidence for the involvement of this protein in human disease (discussed below). In the following sections, we will discuss in detail the regulation of Pak1 and the DRF mDia1 as examples of other Rho GTPase effectors that adopt autoinhibited conformations and propose screening strategies that could lead to the identification of allosteric inhibitors of these effectors.

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