Structural Analysis of Heterotrimeric G Proteins and G Protein‐Coupled Receptor Kinases

Heterotrimeric G proteins and G protein‐coupled receptor kinases (GRKs) are two relatively small families of enzymes that are turned on via direct interactions with active G protein‐coupled receptors (GPCRs), a large and diverse family of integral membrane proteins. Through these interactions, an amazing variety of environmental cues can induce profound changes in G protein‐regulated processes, such as glucose metabolism and regulation of the actin cytoskeleton, as well as GRK‐regulated processes, such as receptor down‐regulation and MAP kinase activation. Crystal structures of G proteins in complex with their effector targets have revealed many insights into the molecular mechanisms by which heterotrimeric G proteins directly regulate the generation of second messengers ( 1–4 ). Structural analysis of GRKs has further demonstrated how heterotrimeric G proteins interact with GRK2 ( 5, 6 ), and, most recently, how GRKs are allosterically activated by GPCRs. Based on the available structural data, we propose that heterotrimeric G proteins and GRKs recognize active GPCRs using a similar mechanism. Support was provided by NIH grants HL071818 and HL086865.