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Design of inhibitors of GPCR kinases (GRKs)
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Katarzyna Sobczyk-Kojiro
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G protein-coupled receptor kinases (GRKs) catalyze the phosphorylation of serine and threonine residues in the cytoplasmic tails and loops of activated GPCRs, targeting these GPCRS for binding by arrestin, which uncouples the GPCRs from G proteins and initiates receptor endocytosis and downregulation. Inhibition of GRK-GPCR interaction thus represents a potential means of augmenting GPCR-mediated signaling, which could have considerable clinical ramifications. In collaboration with John Tesmer (University of Michigan Life Sciences Institute), we are designing peptides based upon the GRK N-terminus (thought to be responsible for GPCR binding) as potential inhibitors of GRK phosphorylation of GPCRs. Since the α-helicity of the GRK N-terminus is known to be important for its interaction with receptor, we are designing peptides with high helical content, either by replacement by residues with higher helical propensity or by covalent, helix-stabilizing modifications.
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Figure 1: Model of opsin in complex with GRK1-derived 13-mer, PR4. PR4 is positioned similarly to the position of the Gαt-Ct peptide bound to opsin (3DQB.pdb). Opsin residues are colored yellow, peptide PR4 is colored cyan.
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