attractive strategy for circumventing tills problem is to engineer a protein of interest to be sensitive to a pharmacological agent of choice. Here, we report a chemical genetic method for regulating the catalytic activity of signaling enzymes with a small molecule. This approach uses the interaction of the antiapoptotic protein Bcl-xL and a BH3 peptide as an autoinhibitory switch that call be controlled with a small molecule. We applied this Strategy to the (guanine nucleotide exchange factor Intersectin, which is a selective activator of the GTPase Cdc42. Replacing Intersectin's regulatory domains with the BH3 peptide/Bcl-xL binding module generated a panel of synthetic GEF constructs that call be activated with a competitive ligand. Importantly, the nucleotide exchange activities of these synthetic Intersectin constructs call be controlled ill a rapid and dose-dependent manner. The modular nature of this strategy should make it useful for engineering other enzymes involved ill signal transduction.