Alzheimer is a neurodegenerative disease that affects 9 million people per year, characterized by loss of brain connectivity leading to deprivation of memory and cognitive functions . The main target of many therapeutic strategies is γ-secretase complex, a multimeric aspartyl protease composed of 4 subunits: presenilin, nicastrin, APH and PEN 2. It plays a fundamental role in the generation of Aβ1-42 from the Amyloid Precursor Protein(APP). Although these drugs are very effective, the majority present severe side effects, most likely due to the role that γ-secretase has in processing other proteins in normal cellular function. Recently, it was discovered that the orphan G protein coupled receptor 3 (GPR3), belonging to GPCRs family, is involved in Alzheimer’s Disease (AD), and act as a regulator of the γ-secretase complex through direct interaction with β-arrestin 2. This interaction promotes the formation of GPR3/β-arrestin 2/APH complex, that is later internalized in endosomes. Although GPR3 can be considered as a new promising therapeutic target for AD, the lack of a known crystal structure hampers a deep characterization of its binding site. Advances in bioinformatics over the last years have revolutionized the characterization of in silico proteins. In this project we plan to use a combined experimental/computational approach, using state of the art and innovative techniques to characterize the interaction of GPR3 with its natural ligand and with β-arrestin 2. The in silico approaches(WP1) will guide the design of the experiments needed for such characterization, in particular by suggesting site-directed mutagenesis experiments(WP2) as in . Then the experimental outcomes will give insights for the improvement of the model, iteratively. Moreover, once the GPR3/β-arrestin 2 complex will be characterized, we will try to design peptides for the selective inhibition of GPR3/β-arrestin 2 complex. The predicted peptides will be then synthesized using both chemical synthesis and biotechnological approaches and experimentally tested (WP3).