W0333

Structural Basis for the Regulation of GPCR Signaling the Crystal Structure of the GKR2 : Gβγ Complex. David Lodowski, Jennifer Barnhill, W. Darrell Capel, Julie A. Pitcher, Robert J. Lefkowitz, John J.G. Tesmer, Chemistry and Biochemistry, Univ. of Texas at Austin, 1 University Station A5300, Austin, TX 78712 USA.

G protein-coupled receptor kinases (GRKs) are responsible for the desensitization of activated G protein-coupled receptors (GPCRs). These receptors are known to regulate heart rate, blood pressure, glucose metabolism, the sensations of smell, taste and sight, and the development of drug dependency. GRK2 is the best studied member of the GRK family, and has been implicated in the progression of heart disease. To better understand the molecular basis for GRK2 activity, we have determined the structure of GRK2 in complex with the heterotrimeric G protein subunits β₁γ₂. This structure elucidates the configuration of the three domains that make up GRK2 and demonstrates how the interaction between its pleckstrin homology (PH) domain and heterotrimeric Gβγ subunits properly orients the kinase domain with respect to its receptor substrate. This interaction also illustrates a potentially widespread mechanism for the recruitment of cytosolic signaling proteins to the plasma membrane.