University of Leipzig
Insights in the Binding mode of Peptides, Activating G Protein Coupled Receptors
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.
By means of ligand modification, receptor mutagenesis, NMR spectroscopy of recombinantly produced receptors and molecular modelling, we have identify the ligand binding site of agonists and antagonists of peptide GPCRs. Furthermore, in combination with X-ray crystallography, cell-free receptor expression and photo-cross-linking we identified the different binding modes of peptide agonists and non peptide antagonists, as well as different downstream pathways.
Knowing the specific binding mode allows the selection of appropriate sites for chemical modification of the ligand, including fluorescence labelling, lipidisation and PEGylation, which significantly modify the activity of the ligand, and leads to effective compounds in vivo. Current application expand the direct effect of the peptide as drugs but allow using them as shuttling systems for intracellular targets, for example in cancer or metabolic diseases.