Project Group C: Modulation of Signal Selectivity
GPCR transmit signals to different transducers, e.g. they activate several classes of G proteins and recruit arrestins after phosphorylation. However, the N terminus of GPCR with large ectodomains may also function as signal itself (trans-signaling) suggesting a new concept in GPCR signal transduction (C04). Projects grouped in C will investigate how the modulation of signal selectivity is performed on a molecular level and which are the consequences. Most recent evidence indicates that biased ligands elicit divergent structural changes in the ligand binding pocket which are allosterically translated to the intracellular transducer binding site, thus leading to biased signaling. The structural dynamics of biased signaling will be studied at M2 receptor, as it is by far the best-studied receptor in terms of allosteric modulation (C05). The prototypical β-adrenergic receptors have been well-characterized in diverse signaling pathways being an ideal model for studying signaling selectively not only at the cell membrane but also in intracellular compartments (C03). C01 uses computational approaches to identify possible receptor G-protein/arrestin binding motifs conserved during evolution in sequence and space.