G protein-coupled receptor kinases (GRKs)
GRKs are Ser/Thr kinases responsible for homologous desensitization of GPCRs, an adaptive process by which activated receptors are rapidly uncoupled from heterotrimeric G proteins. There are seven isoforms (GRK1-7) in vertebrates, representing three subfamilies. One well-characterized member of this family is GRK2, also known as β-adrenergic receptor kinase 1. GRK2 is not only important for myocardiogenesis and regulation of heart contractility, but also implicated in the progression of congestive heart failure. In 2003, we reported the atomic structure of GRK2 in complex with its G protein regulator Gβγ, the first of a GRK. Subsequently, we have described the structure of GRK6 (2006), an enzyme involved in motor neuron function and a potential drug target for the treatment of Parkinson’s disease, and of GRK1 (2008), also known as rhodopsin kinase, which regulates the amplitude of the light response in rod cells. An important goal of our lab has been to understand the regulation of these enzymes by activated GPCRs. Most recently, we have determined the structure of GRK6 in a closed conformation, revealing the receptor binding site and a unique allosteric mechanism for activation of kinase activity. Ongoing efforts are to structurally characterize GRKs in complex with their physiological targets: activated GPCRs. Understanding the structure of a GPCR in its activated state is one of the holy grails of modern pharmacology, and GRK complexes may facilitate this quest.