title: Peptide inhibitors of G protein-coupled receptor kinases.
abstract: G protein-coupled receptor kinases (GRKs) are regulatory enzymes involved in the modulation of seven-transmembrane-helix receptors. In order to develop specific inhibitors for these kinases, we synthesized and investigated peptide inhibitors derived from the sequence of the first intracellular loop of the beta2-adrenergic receptor. Introduction of changes in the sequence and truncation of N- and C-terminal amino acids increased the inhibitory potency by a factor of 40. These inhibitors not only inhibited the prototypical GRK2 but also GRK3 and GRK5. In contrast there was no inhibition of protein kinase C and protein kinase A even at the highest concentration tested. The peptide with the sequence AKFERLQTVTNYFITSE inhibited GRK2 with an IC50 of 0.6 microM, GRK3 with 2.6 microM and GRK5 with 1.6 microM. The peptide inhibitors were non-competitive for receptor and ATP. These findings demonstrate that specific peptides can inhibit GRKs in the submicromolar range and suggest that a further decrease in size is possible without losing the inhibitory potency.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Winstel
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Ihlenfeldt
authors.forename: Günther
authors.initials: G
authors.lastname: Jung
authors.forename: Cornelius
authors.initials: C
authors.lastname: Krasel
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
mesh_terms: D000595:Amino Acid Sequence; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D000242:Cyclic AMP; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins