Prof. Dr. Annette Beck-Sickinger, Leipzig University, Germany

"G Protein-Coupled Receptors: From Struc­ture to Cell Specific Drug Targeting"

Peptides hormones play an important role in the regulation of manifold activities in the body. Many of them transmit their activity through G protein-coupled receptors (GPCR), which are among the most promising drug targets nowadays. However, in addition to their direct activity, indirect mechanisms have been shown to play a role. This includes their use as drug shuttles, e. g. in tumour targeting. Accordingly, in addition to ligand binding, internalization has to be addressed and to be studied, including arrestin recruit­ment. The neuropeptide Y/pancreatic polypeptide family contains 36 amino acid pep­tides that bind in human to four different so-called Y-receptors. By a combination of X-ray analysis, cryo-EM, NMR, molecular modelling and crosslinking combined with mass spectrometry, we have recently identified the distinct binding modes of NPY peptides to their Y-receptors. Neuropeptide Y receptors have been shown to play a relevant role in the regulation of food intake. Furthermore, they participate in adipogenesis and some of them are overexpressed in tumours. By knowing the receptor bound structure, specific ligands as well as peptide-drug conjugates have been designed to selectively address Y receptors in different tissues including allo­steric modulators.