Using structural information of peptides, derived from NMR spectroscopy, in pharmaceutical chemistry

The significance of information gained from the solution structure of pepti des for pharmaceutical research is demonstrated with two examples: the neur opeptide Y (N PY) hormone system and a undecapeptide designed for use as a chemical sensor. In the case of NPY, the structure of the homodimer and the mode of membrane association was determined. Thereby, it was discovered th at the membrane/NPY interface is formed by the same hydrophobic residues th at constitute the homodimer interface. Furthermore, in the membrane-bound s tate, the C-terminal helix is stabilized, which is of special functional im portance for the C-terminal tetrapeptide. Receptor-subtype specificity of N PY mutants may be explained through pre-orientation of residues relative to the different membrane compartments. In the case of the undecapeptide desi gned for use in a chemical sensor, structural information from NMR helped u s to design and optimize a peptide whose unligated form is unstructured in solution but adopts a unique helical fold upon addition of sulfate. The sul fate binding pocket is formed by the N-terminal first turn.