Classical drug design approaches rely on finding an accessible binding site whose occupancy can exert a pharmacological effect. This condition eliminates many membrane proteins from being “druggable”. In a new venue, “Lysosomal Targeting Chimeras” (LYTACs) use lysosome-shuttling receptors to establish targeted degradation of membrane proteins. In LYTACs, a chimeric ligand comprises a ligand targeting a membrane protein fused to a ligand of a lysosome-shuttling receptor. This chimera binds simultaneously to the lysosome receptor and the target membrane protein. The lysosome receptor shuttles the cargo to the lysosomal compartments and the target protein will be degraded, which will lead to the pharmacological effect. In this project, the major goal is to study ligand binding to lysosomal receptors and then to use the mechanistic insight to develop new chimeric ligands targeting undruggable membrane proteins.