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John Tesmer Research Group

Structure and Function of G protein-coupled receptor kinases (GRKs)

One of the primary areas of interest in the Tesmer lab involves a family of seven vertebrate kinases that regulated the signaling of activated GPCRs. In 2003, the lab published the structure of the GRK2-Gβγ complex, the first of a GRK and the first of G protein βγ subunits in complex with an effector (1). In 2005, the Tesmer lab reported the structure of the Gαq-GRK2-Gβγ complex (2), providing a snapshot of activated Gα and Gβγ subunits at the membrane as they engage a common effector target. This was also the first structure of Gαq. The lab went on to characterize GRKs from two other subfamilies, GRK6 (3), GRK1/rhodopsin kinase, and most recently GRK5 (4). These efforts helped to identify a site on the GRK kinase domain that forms the docking site for activated GPCRs. Structural characterization of GRK-GPCR complexes are a high priority goal.
Project 2
Publications

  1. Lodowski DT, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJG: Keeping G proteins at bay: a complex between G protein-coupled receptor kinase 2 and Gβγ, Science 2003, 300: 1256-1262. PMID: 12764189

  2. Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJG: Snapshot of activated G proteins at the membrane: the Gαq-GRK2-Gβγ complex. Science 2005, 310: 1686-1690. PMID: 16339447

  3. Boguth CA, Singh P, Huang C, Tesmer JJG: Molecular basis for activation of G protein-coupled receptor kinases. EMBO J, 2010, 29: 3249-59. PMCID: PMC2957210

  4. Homan KT, Waldschmidt H, Glukhova A, Cannavo A, Song J, Cheung JY, Koch WJ, Larsen SD, Tesmer JJG: Crystal structure of G protein-coupled receptor kinase 5 in complex with a rationally designed inhibitor. J. Biol. Chem. 2015, 290: 20649-59. PMID: 26032411. PMCID: PMC4543626